Losartan plus-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOSARTAN PLUS-TEVA (LosartanPLUS-Teva)

Composition:

Active substances: losartan potassium, hydrochlorothiazide;

One film-coated tablet contains losartan potassium 50 mg, hydrochlorothiazide 12.5 mg or one film-coated tablet contains losartan potassium 100 mg, hydrochlorothiazide 25 mg;

Excipients:

Core: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, magnesium stearate;

Coating: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc, yellow iron oxide (E 172).

Pharmaceutical form.

Film-coated tablets.

Main physicochemical characteristics:

Tablets 50/12.5 mg: yellow, biconvex, oval tablets, embossed with "5" and "0" on one side and a break line on both sides. The break line is intended solely to facilitate tablet splitting for ease of swallowing and should not be used to divide the tablet into equal doses;

Tablets 100/25 mg: yellow, biconvex, oval tablets, embossed with "1" and "00" on one side and a break line on both sides. The break line is intended solely to facilitate tablet splitting for ease of swallowing and should not be used to divide the tablet into equal doses.

Pharmacotherapeutic group.

Angiotensin II receptor antagonists and diuretics. ATC code C09DA01.

Pharmacological Properties

Pharmacodynamics

Losartan Potassium / Hydrochlorothiazide

It is known that the components of the medicinal product losartan potassium / hydrochlorothiazide exhibit an additive effect in reducing arterial pressure, providing together a greater antihypertensive effect than each component alone. This effect is considered to result from the complementary actions of both components of the medicinal product. In addition, due to its diuretic action, hydrochlorothiazide increases renin activity, enhances aldosterone secretion, reduces serum potassium levels, and increases angiotensin II levels in blood plasma. Losartan blocks all physiologically significant effects of angiotensin II and, through aldosterone suppression, helps reduce potassium ion losses induced by the diuretic.

It has been established that losartan exerts a weak transient uricosuric effect. It is known that hydrochlorothiazide causes a moderate increase in plasma uric acid levels; the combination of losartan and hydrochlorothiazide helps reduce diuretic-induced hyperuricemia.

The antihypertensive effect of losartan potassium / hydrochlorothiazide lasts for 24 hours and is maintained during continuous treatment. The drug has no clinically significant effect on heart rate. It is known that after 12 weeks of treatment with the combination of losartan potassium and hydrochlorothiazide (50 mg / 12.5 mg), the minimum seated diastolic blood pressure decreased on average by 13.2 mm Hg.

Losartan potassium / hydrochlorothiazide is an effective agent for reducing arterial pressure in both men and women, individuals of non-African and other racial backgrounds, younger patients, and elderly patients (>65 years) regardless of the severity of hypertension.

Losartan

Losartan is a synthetic angiotensin II receptor antagonist (AT1 type) for oral administration. Angiotensin II is a potent vasoconstrictor, the primary active hormone of the renin-angiotensin system, and an important factor 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), mediating several important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation. Losartan selectively blocks AT1 receptors. In in vitro and in vivo studies, losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block all physiologically significant effects of angiotensin II, regardless of its source or synthesis pathway.

Losartan has no agonistic effect and does not block other hormone receptors or ion channels that play a key role in cardiovascular regulation. Additionally, losartan does not inhibit angiotensin-converting enzyme (kinase II), the enzyme responsible for bradykinin breakdown. Therefore, there is no enhancement of bradykinin-mediated adverse effects.

With losartan administration, suppression of the negative feedback of angiotensin II on renin secretion is observed, leading to increased plasma renin activity. Elevated renin activity results in increased plasma angiotensin II concentration. Despite this, antihypertensive activity and reduced plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan therapy, plasma renin activity and angiotensin II concentration return to baseline values within 3 days.

Losartan and its main active metabolite exhibit higher affinity for AT1 receptors than for AT2 receptors. On a mass basis, the active metabolite is 10–40 times more potent than losartan.

It is known that the incidence of cough in patients receiving losartan or hydrochlorothiazide is similar and significantly lower than with angiotensin-converting enzyme (ACE) inhibitors.

In non-diabetic patients with arterial hypertension and proteinuria, treatment with losartan potassium was associated with a significant reduction in proteinuria, fractional albumin excretion, and plasma IgG levels. Losartan maintains glomerular filtration rate and reduces filtration fraction. Overall, losartan contributes to a decrease in plasma uric acid concentration (typically <0.4 mg/dL), which persists during long-term therapy.

Losartan does not affect autonomic reflexes and has no sustained effect on plasma norepinephrine levels.

In patients with left ventricular dysfunction, doses of losartan 25 mg and 50 mg were associated with positive hemodynamic and neurohormonal effects, characterized by increased cardiac index and reduced pulmonary capillary wedge pressure, systemic vascular resistance, mean arterial pressure, and heart rate, as well as decreased circulating aldosterone and norepinephrine levels. The occurrence of arterial hypotension in heart failure patients is dose-dependent.

In two large placebo-controlled trials (ONTARGET and NEPHRON-D), the benefits of concomitant use of ACE inhibitors and angiotensin II receptor antagonists were evaluated. The studies showed that concomitant use of ACE inhibitors with angiotensin II receptor antagonists in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage did not provide significant positive effects on kidney function and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Therefore, concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

In the ALTITUDE trial, designed to assess the benefits of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor antagonists in patients with type 2 diabetes and chronic kidney and/or cardiovascular disease, a high risk of adverse outcomes was observed, leading to early termination of the study. Cardiovascular death and stroke occurred more frequently in the aliskiren group than in the placebo group. Additionally, adverse events and serious side effects, such as hyperkalemia, arterial hypotension, and renal dysfunction, were more common in the aliskiren group than in the placebo group.

Hydrochlorothiazide

Hydrochlorothiazide belongs to the group of thiazide diuretics; the mechanism of its antihypertensive action 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. Due to its diuretic effect, hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and enhances aldosterone secretion, leading to increased urinary excretion of potassium and bicarbonate and decreased serum potassium levels. It is likely that concomitant use of angiotensin II receptor antagonists, through blockade of the renin-aldosterone system, reduces potassium loss associated with thiazide diuretic use.

After oral administration, the diuretic effect begins within two hours, reaches its peak approximately after 4 hours, and lasts for about 6–12 hours. The antihypertensive effect persists for up to 24 hours.

Pharmacokinetics

Losartan

Absorption. After oral administration, losartan is well absorbed and undergoes presystemic metabolism, forming an active carboxylic acid metabolite and several inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. The mean peak plasma concentrations of losartan and its active metabolite are reached within 1 hour and 3–4 hours, respectively. Administration with food did not result in any clinically significant effect on plasma losartan concentrations.

Distribution. Over 99% of losartan and its active metabolite are bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Animal studies indicate that losartan penetrates the blood-brain barrier in negligible amounts or not at all.

Biological Transformation. Approximately 14% of the administered dose of losartan, whether intravenous or oral, is converted into the active metabolite. After oral and intravenous administration of radiolabeled 14C-losartan potassium, radioactivity in circulating plasma was primarily associated with losartan and its active metabolite. In addition to the active metabolite, inactive metabolites are formed, including two major ones resulting from hydroxylation of the butyl side chain, and one minor metabolite—N-2-tetrazole-glucuronide.

Elimination. The plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. The renal clearance of losartan and its active metabolite is nearly 74 mL/min and 26 mL/min, respectively. After oral administration, approximately 4% of the dose is excreted unchanged in urine and about 6% as the active metabolite. Losartan and its active metabolite exhibit linear pharmacokinetics after oral administration of losartan potassium at doses up to 200 mg. Plasma concentrations of losartan and its active metabolite decline polyexponentially after oral administration, with terminal elimination half-lives of approximately 2 hours and 6–9 hours, respectively. With a daily dose of 100 mg, no significant accumulation of losartan or its active metabolite in plasma is observed. Elimination of losartan and its metabolites occurs via both urine and bile. After oral administration of radiolabeled 14C-losartan in humans, approximately 35% of the radioactive dose is recovered in urine and about 58% in feces.

Hydrochlorothiazide

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

Elimination. Hydrochlorothiazide is not metabolized and is rapidly excreted unchanged by the kidneys. Plasma level analysis over at least 24 hours has shown that the plasma elimination half-life ranges from 5.6 to 14.8 hours. After oral administration, at least 61% of the dose is excreted unchanged in urine within 24 hours.

Special Patient Populations

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

After oral administration, plasma concentrations of losartan and its active metabolite in patients with mild to moderate alcoholic cirrhosis of the liver were 5-fold and 1.7-fold higher, respectively, compared to young healthy volunteers.

Pharmacokinetic studies have shown that AUC of losartan does not differ between Japanese and non-Japanese men. However, AUC of the carboxylic acid metabolite (E-3174) differed between the two groups: a 1.5-fold increase in exposure was observed in Japanese individuals compared to non-Japanese individuals. The clinical significance of these findings is unknown.

Losartan and its active metabolite are not removed from the body during hemodialysis.

Clinical characteristics.

Indications.

Essential hypertension in patients in whom monotherapy with losartan or hydrochlorothiazide does not provide adequate control of arterial pressure.

Contraindications.

• Hypersensitivity to losartan, sulfonamide derivatives (such as hydrochlorothiazide), or to any component of the medicinal product.
• Refractory hypokalemia or hypercalcemia.
• Severe hepatic impairment, cholestasis, and conditions associated with biliary obstruction.
• Refractory hyponatremia.
• Symptomatic hyperuricemia/podagra.
• Severe renal impairment (creatinine clearance <30 mL/min).
• Anuria.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or lactation").
• Breastfeeding.
• Pediatric age.
• Concomitant use of the medicinal product with aliskiren-containing agents in patients with diabetes mellitus or renal impairment (eGFR [estimated glomerular filtration rate] <60 mL/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Losartan

It has been reported that rifampicin and fluconazole reduce plasma levels of the active metabolite of losartan. The clinical significance of this interaction has not been studied.

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

As with other medicinal products affecting sodium excretion, lithium clearance may be reduced. Therefore, careful monitoring of serum lithium levels is necessary if concomitant use of lithium salts with angiotensin II receptor antagonists is required.

When angiotensin II receptor antagonists are administered concomitantly with non-steroidal anti-inflammatory drugs [NSAIDs] (e.g., selective cyclooxygenase-2 [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 with NSAIDs may increase the risk of worsening renal function, potentially leading to acute renal failure, and may elevate serum potassium levels, particularly in patients with pre-existing renal impairment at the start of treatment. The combination should be used cautiously in elderly patients. Adequate hydration of the patient should be ensured, and renal function should be monitored after initiation of combination therapy and periodically thereafter.

In some patients with impaired renal function receiving non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors, concomitant use of angiotensin II receptor antagonists may lead to further deterioration of renal function. This effect is usually reversible.

Results from clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with increased incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to monotherapy with any RAAS blocker.

Concomitant use with agents such as tricyclic antidepressants, antipsychotics, baclofen, amifostine, whose primary or secondary effect is lowering of blood pressure, may increase the risk of developing arterial hypotension.

Hydrochlorothiazide

The following interactions may occur with concomitant use of thiazide diuretics.

Alcohol, barbiturates, narcotics, or antidepressants

May potentiate orthostatic hypotension.

Antidiabetic agents (oral or insulin)

Thiazide drugs may impair glucose tolerance. Dose adjustment of antidiabetic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis resulting from possible functional renal impairment associated with hydrochlorothiazide.

Other antihypertensive agents

Additive effect.

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired by anion-exchange resins. Single doses of cholestyramine or colestipol bind hydrochlorothiazide and reduce its gastrointestinal absorption by approximately 85% and 43%, respectively.

Corticosteroids, adrenocorticotropic hormone (ACTH)

Increased risk of electrolyte imbalance, particularly hypokalemia.

Pressor amines (e.g., adrenaline)

May reduce the effectiveness of pressor amines, although not to such an extent as to necessitate discontinuation.

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

May potentiate the effect of muscle relaxants.

Lithium preparations

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

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

Dose adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be necessary. The frequency of hypersensitivity reactions to allopurinol may increase with concomitant use of thiazides.

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

Due to reduced gastrointestinal motility and delayed gastric emptying, bioavailability of thiazide diuretics may be increased.

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 their toxic effects on the central nervous system.

Methyldopa

Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant use of cyclosporine may increase the risk of hyperuricemia and complications such as gout.

Cardiac glycosides

Hypokalemia or hypomagnesemia induced by thiazide therapy may predispose to cardiac arrhythmias associated with cardiac glycoside use.

Medicinal products whose efficacy is influenced by changes in serum potassium levels

Periodic monitoring of serum potassium levels and ECG should be recommended when losartan/hydrochlorothiazide is used concomitantly with medicinal products whose efficacy is affected by changes in serum potassium levels (such as cardiac glycosides and antiarrhythmic agents), or with the following agents known to induce polymorphic ventricular tachycardia (torsades de pointes), including certain antiarrhythmic drugs, since hypokalemia is a contributing factor to the development of torsades de pointes:

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

Calcium salts

Thiazide diuretics may increase serum calcium levels by reducing its excretion. If calcium-containing dietary supplements are required, serum calcium levels should be monitored and adjusted accordingly.

Effect on laboratory test results

Since thiazides affect calcium metabolism, they may influence the assessment of parathyroid gland function.

Carbamazepine

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

Iodinated contrast agents

In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, especially with high doses of iodinated contrast agents.

Fluid volume should be restored prior to administration of such agents.

Amphotericin B (parenteral), stimulant laxatives, or glycyrrhizin (from licorice root)

Hydrochlorothiazide may disturb electrolyte balance, particularly causing hypokalemia.

Special precautions for use.

Related to losartan

Angioedema

Patients with a history of angioedema (swelling of the face, lips, pharynx, and/or tongue) should be under close supervision (see section "Adverse reactions").

Intestinal angioedema

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

Arterial hypotension and reduced intravascular volume

Symptomatic hypotension may occur in patients with reduced intravascular volume and/or hyponatremia caused by intensive diuretic therapy, dietary salt restriction, diarrhea, or vomiting, particularly after the first dose of the drug. These conditions should be corrected prior to initiating therapy (see sections "Dosage and administration" and "Contraindications").

Electrolyte imbalance

Electrolyte imbalance is common in patients with renal dysfunction, with or without concomitant diabetes mellitus. Plasma potassium levels and creatinine clearance should be closely monitored, especially in patients with heart failure and creatinine clearance of 30–50 mL/min.

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

Hepatic impairment

Based on pharmacokinetic data indicating significantly increased plasma concentrations of losartan in patients with hepatic cirrhosis, losartan/hydrochlorothiazide should be used with caution in patients with mild to moderate hepatic impairment. Experience with losartan in patients with severe hepatic impairment is lacking. Therefore, losartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see sections "Contraindications" and "Pharmacological properties").

Renal impairment

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

As with other medicinal products affecting the renin-angiotensin-aldosterone system, increased blood urea and serum creatinine levels have been reported in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney. These changes in renal function may be reversible and resolve upon discontinuation of therapy. Losartan should be prescribed with caution in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Renal transplantation

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

Primary hyperaldosteronism

Antihypertensive agents acting via inhibition of the renin-angiotensin system are generally ineffective in patients with primary hyperaldosteronism. Therefore, losartan potassium/hydrochlorothiazide tablets are not recommended for such patients.

Ischemic heart disease and cerebrovascular disease

As with any antihypertensive agent, losartan may cause a significant reduction in blood pressure in patients with ischemic heart disease or cerebrovascular insufficiency, which may lead to myocardial infarction or stroke.

Heart failure

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

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

Losartan/hydrochlorothiazide should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Ethnic factors

It is known that angiotensin-converting enzyme inhibitors, losartan, and other angiotensin antagonists are less effective in reducing blood pressure in black patients compared to patients of other races. This is likely due to the higher prevalence of low renin activity among black patients with arterial hypertension.

Pregnancy

This medicinal product should not be used in pregnant women or women planning to become pregnant. If therapy with angiotensin II receptor antagonists is considered necessary, alternative antihypertensive therapy with an established safety profile during pregnancy should be prescribed to women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use in pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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

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

If dual RAAS blockade is considered essential, it should be performed only under specialist supervision with careful monitoring of renal function, fluid and electrolyte balance, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Related to hydrochlorothiazide

Arterial hypotension and disturbances of fluid and electrolyte balance

As with any antihypertensive agents, symptomatic arterial hypotension may occur in individual patients. These patients should be monitored for clinical signs of fluid and electrolyte imbalance, including hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may occur with concomitant diarrhea or vomiting. In such patients, serum electrolyte levels should be monitored regularly at defined intervals. In hot weather, hyponatremia due to dilution may occur in patients suffering from edema.

Metabolic and endocrine effects

Thiazide-type drugs may impair glucose tolerance. Doses of antidiabetic agents, including insulin, may require adjustment (see section "Interaction with other medicinal products and other forms of interaction"). Latent diabetes mellitus may become manifest during thiazide therapy. Thiazide drugs may reduce calcium excretion in urine and may cause occasional slight increases in serum calcium levels. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide therapy should be discontinued prior to parathyroid function testing.

Use of thiazide diuretics may provoke increased plasma cholesterol and triglyceride levels.

Thiazide drugs may promote hyperuricemia and/or gout in some patients. Since losartan reduces uric acid levels, the use of losartan in combination with hydrochlorothiazide reduces diuretic-induced hyperuricemia.

Visual disturbances

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma: Medicinal products containing sulfonamides 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 sudden onset of decreased visual acuity or eye pain and usually occur within hours or weeks after 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, emergency medical or surgical treatment may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

Hepatic impairment

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

Losartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see sections "Contraindications" and "Pharmacological properties").

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative exposure to hydrochlorothiazide was observed in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a mechanism contributing to NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly examine their skin for new lesions and promptly report any suspicious skin changes. To reduce the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and ultraviolet radiation or using appropriate protective measures when exposed to solar or ultraviolet rays. Suspicious skin lesions should be promptly evaluated with histological examination of biopsy specimens. Re-evaluation of hydrochlorothiazide use may be necessary in patients with a history of NMSC (see also section "Adverse reactions").

Acute respiratory toxicity

Very rare, severe 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 lung condition, and hypotension. If ARDS is suspected, this drug should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Other warnings

Hypersensitivity reactions may occur in patients taking thiazide diuretics, even in the absence of a history of allergy symptoms or bronchial asthma. Exacerbation or progression of systemic lupus erythematosus has been reported during thiazide therapy.

Related to excipients

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

Use during pregnancy or breastfeeding.

Pregnancy

Angiotensin II receptor antagonists (ARBs)

The use of ARBs is contraindicated during pregnancy (see sections "Contraindications" and "Special precautions for use"). Epidemiological data on the teratogenic risk of ARBs during the first trimester of pregnancy are insufficient and do not exclude an increased risk of teratogenicity. Women planning pregnancy should be switched to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy occurs, ARB therapy should be discontinued immediately and alternative therapy initiated if necessary. Use of ARBs during the second and third trimesters of pregnancy is associated with enhanced fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If ARBs were used from the second trimester of pregnancy, ultrasound assessment of renal function and skull ossification of the newborn should be performed.

Newborns whose mothers received ARB therapy during pregnancy should be closely monitored for the risk of arterial hypotension (see section "Special precautions for use").

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy is limited, particularly in the first trimester. Animal studies are also limited. It is known that hydrochlorothiazide crosses the placental barrier. Due to its pharmacological mechanism of action, hydrochlorothiazide use during the second and third trimesters of pregnancy may adversely affect fetoplacental perfusion and lead to disorders in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat edema of pregnancy, gestational hypertension, or preeclampsia, as such use is associated with the risk of reduced plasma volume and placental hypoperfusion without any beneficial effect on disease course. Hydrochlorothiazide should not be used to treat essential hypertension in pregnant women.

Breastfeeding

The use of potassium losartan/hydrochlorothiazide during breastfeeding is contraindicated.

If treatment with this medicinal product is necessary, breastfeeding should be discontinued. An alternative medicinal product with an established safety profile should be used during breastfeeding.

Effect on ability to drive and use machines.

No studies on the effect on the ability to drive or operate machinery have 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

The medicinal product can be administered independently of food intake. The tablet should be swallowed with water.

The medicinal product may be prescribed in combination with other antihypertensive agents (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

The combination of losartan and hydrochlorothiazide is not used as initial therapy, but is prescribed to patients in whom adequate blood pressure control cannot be achieved with monotherapy using either losartan or hydrochlorothiazide.

It is recommended to determine the dosage by individually titrating the doses of each component of the medicinal product (losartan and hydrochlorothiazide). In clinically appropriate cases, direct transition from monotherapy to fixed-dose combination therapy may be considered for patients who do not achieve adequate blood pressure control.

The usual initial and maintenance dose is 50 mg losartan and 12.5 mg hydrochlorothiazide once daily. For patients who do not achieve an adequate therapeutic response, the dose of the combination may be increased to 100 mg losartan / 25 mg hydrochlorothiazide once daily.

Maximum dose: 1 tablet of 100 mg losartan / 25 mg hydrochlorothiazide once daily. A stable antihypertensive effect is generally achieved within 3–4 weeks after initiation of treatment.

Use in patients with renal impairment and patients undergoing hemodialysis

No initial dose adjustment is required in patients with moderate renal impairment (i.e., creatinine clearance of 30–50 mL/min). Administration of tablets containing losartan and hydrochlorothiazide is not recommended in patients undergoing hemodialysis. The use of this medicinal product is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see section "Contraindications").

Use in patients with intravascular hypovolemia

Intravascular hypovolemia and/or hyponatremia should be corrected prior to initiating treatment with this medicinal product.

Use in patients with hepatic impairment

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

Use in elderly patients

Dose adjustment in elderly patients is generally not required.

Children

Safety and efficacy of losartan/hydrochlorothiazide in children (under 18 years of age) have not been established – the use of this medicinal product in children is contraindicated.

Overdose

There are no data on specific treatment for overdose with this medicinal product. Symptomatic and supportive treatment should be administered as needed. In case of overdose, treatment with the medicinal product should be discontinued and the patient should be closely monitored. If the medicinal product has been recently ingested, induce vomiting and implement measures to correct dehydration, electrolyte imbalances, hepatic encephalopathy, and arterial hypotension according to established treatment guidelines.

Losartan. Data on losartan overdose in humans are limited. The most likely manifestations of overdose are arterial hypotension and tachycardia. Bradycardia may develop as a result of parasympathetic (vagal) stimulation. In cases of symptomatic arterial 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. When digitalis preparations are used concomitantly, hypokalemia may predispose to cardiac arrhythmias. Hydrochlorothiazide is removed by hemodialysis, but the extent of removal is not well established.

Adverse Reactions

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

In controlled clinical trials of essential hypertension, the only adverse reaction associated with the use of the combination drug that occurred more frequently than with placebo was dizziness.

During the post-marketing period, the following adverse reactions have been reported:

Hepatobiliary system: hepatitis;

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

The adverse reactions listed below were observed during administration of the active substances as monotherapy and may also occur during treatment with the combination drug losartan potassium / hydrochlorothiazide.

Associated with losartan

Blood and lymphatic system disorders: anemia, Schönlein–Henoch purpura, ecchymosis, hemolysis, thrombocytopenia.

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

Ear and labyrinth disorders: vertigo, tinnitus.

Eye disorders: blurred vision, burning or prickling sensation in the eyes, conjunctivitis, decreased visual acuity.

Gastrointestinal disorders: abdominal pain, nausea, vomiting, diarrhea, dyspepsia, toothache, dry mouth, flatulence, gastritis, pancreatitis, constipation, intestinal obstruction, intestinal angioedema.

General disorders: asthenia, increased fatigue, chest pain, facial swelling, fever, flu-like symptoms, malaise, edema.

Hepatobiliary disorders: hepatic function abnormalities.

Immune system disorders: hypersensitivity – anaphylactic reactions, angioedema, including laryngeal and glottis edema leading to airway obstruction, and/or facial, lip, pharyngeal, and/or tongue swelling; some of these patients had a history of angioedema associated with other medicinal products, including ACE inhibitors.

Metabolism and nutrition disorders: anorexia, gout.

Musculoskeletal and connective tissue disorders: muscle cramps, back pain, leg pain, myalgia, arm and shoulder pain, joint swelling, knee pain, musculoskeletal pain, joint stiffness, arthralgia, arthritis, hip joint pain, fibromyalgia, muscle weakness, rhabdomyolysis.

Nervous system disorders: headache, dizziness, nervousness, paresthesia, peripheral neuropathy, tremor, migraine, syncope, dysgeusia.

Psychiatric disorders: insomnia, anxiety, anxiety disorder, panic disorder, confusion, depression, unusual dreams, sleep disorders, somnolence, memory impairment.

Renal and urinary disorders: renal function abnormalities, renal failure, nocturia, frequent urination, urinary tract infections.

Reproductive system disorders: decreased libido, erectile dysfunction / impotence.

Respiratory, thoracic and mediastinal disorders: cough, upper respiratory tract infections, nasal congestion, sinus disease, sinusitis, throat discomfort, pharyngitis, laryngitis, dyspnea, bronchitis, epistaxis, rhinitis, respiratory congestion.

Skin and subcutaneous tissue disorders: alopecia, dermatitis, dry skin, erythema, hyperemia, photosensitivity, pruritus, rash, urticaria, increased sweating.

Vascular disorders: vasculitis, dose-dependent orthostatic effects.

Laboratory findings: hyperkalemia, slight decrease in hematocrit and hemoglobin, hypoglycemia, slight increase in serum urea and creatinine, increased liver enzymes and bilirubin, hyponatremia.

Associated with hydrochlorothiazide

Blood and lymphatic system disorders: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia.

Immune system disorders: anaphylactic reactions.

Metabolism and nutrition disorders: anorexia, hyperglycemia, hyperuricemia, hypokalemia, hyponatremia.

Psychiatric disorders: insomnia.

Nervous system disorders: headache.

Eye disorders: transient visual blurring, xanthopsia, choroidal effusion, acute myopia, acute angle-closure glaucoma.

Vascular disorders: necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: respiratory distress syndrome (including pneumonitis and pulmonary edema), acute respiratory distress syndrome.

Gastrointestinal disorders: sialadenitis, spasms, gastric irritation, nausea, vomiting, diarrhea, constipation.

Hepatobiliary disorders: jaundice (intrahepatic cholestasis), pancreatitis.

Skin and subcutaneous tissue disorders: photosensitivity, urticaria, toxic epidermal necrolysis, systemic lupus erythematosus.

Musculoskeletal and connective tissue disorders: muscle cramps.

Benign, malignant and unspecified neoplasms (including cysts and polyps): non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Renal and urinary disorders: glucosuria, interstitial nephritis, renal function abnormalities, renal failure.

General disorders: fever, dizziness.

Description of selected adverse reactions

Non-melanoma skin cancer. Epidemiological data have shown an association between the occurrence of non-melanoma skin cancer and cumulative dose of hydrochlorothiazide (see section "Special precautions for use").

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister. Tablets 50 mg/12.5 mg: 3, 6, or 9 blisters per cardboard box; tablets 100 mg/25 mg: 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturers: JSC "Pharmaceutical Plant Teva".

Teva Pharma S.L.U.

Manufacturers' addresses and locations of their business activities:

Site 1; Pallagi Str. 13, H-4042 Debrecen, Hungary.

Poligono Industrial Malpica c/C No. 4, 50016, Zaragoza, Spain.