Presartan® h-50

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRESTARAN® H-50 (PRESARTAN® H-50)

Composition:

Active substances: losartan potassium, hydrochlorothiazide;

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

Excipients: lactose monohydrate; microcrystalline cellulose; pregelatinized starch; corn starch; colloidal anhydrous silicon dioxide; magnesium stearate;

Film coating: hydroxypropylmethylcellulose, titanium dioxide (E 171), talc, polyethylene glycol 6000, quinoline yellow (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, oval-shaped, biconvex film-coated tablets.

Pharmacotherapeutic group.

Combined antihypertensive agent (angiotensin II receptor antagonist type AT₁ and diuretic). ATC code C09D A01.

Pharmacological properties.

Pharmacodynamics

Potassium losartan/hydrochlorothiazide

It is known that the components of the medicinal product, potassium losartan/hydrochlorothiazide, exhibit an additive effect in reducing arterial pressure, providing together a greater antihypertensive action than each component alone. This effect is considered to be the result of the complementary action of both components of the medicinal product. In addition, due to its diuretic effect, hydrochlorothiazide increases renin activity, increases aldosterone secretion, reduces potassium content, and increases angiotensin II levels in blood serum. Administration of losartan blocks all physiologically significant effects of angiotensin II and, through inhibition of aldosterone, contributes to a reduction in potassium ion losses caused 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 uric acid levels in blood plasma; the combination of losartan and hydrochlorothiazide helps reduce hyperuricemia associated with diuretic use.

The antihypertensive effect of potassium losartan/hydrochlorothiazide lasts for 24 hours and is maintained during continuous treatment. The medicinal product does not clinically significantly affect heart rate. It is known that after 12 weeks of treatment with the combination of potassium losartan and hydrochlorothiazide (50 mg/12.5 mg), the minimum diastolic blood pressure value in the sitting position decreased on average by 13.2 mm Hg.

Potassium losartan/hydrochlorothiazide is an effective agent for reducing blood pressure in men and women, individuals of non-African descent and representatives of other races, younger patients and elderly individuals (>65 years) at any severity level of hypertension.

Losartan

Losartan is a synthetic angiotensin II receptor antagonist (AT1 type) for oral administration. Angiotensin II is a potent vasoconstrictor and is the active hormone of the renin-angiotensin system (RAS), being one of the most important factors in the pathophysiology of arterial hypertension. Angiotensin II binds to the AT1 receptor, found in many tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, and heart), determining a number of important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation.

Losartan selectively binds to 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.

The active substance selectively binds to the AT1 receptor, does not bind to or block other hormone receptors or ion channels. Losartan does not inhibit ACE (kininase II)—the enzyme responsible for bradykinin breakdown. As a result, effects not directly related to AT1 receptor blockade, such as enhanced effects mediated by bradykinin, are not associated with losartan use.

During losartan administration, the removal of the negative feedback reaction of angiotensin II on renin secretion leads to an increase in plasma renin activity. This increase in activity leads to elevated angiotensin II levels in plasma. Although such an increase occurs, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and angiotensin II levels return to baseline values within 3 days.

Both losartan and its main metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more potent than losartan.

According to a study specifically designed to evaluate the incidence of cough in patients taking losartan compared to patients 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.

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

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

In patients with left ventricular failure receiving doses of losartan 25 mg and 50 mg, a positive hemodynamic and neurohormonal effect was observed, characterized by an increase in cardiac index and a reduction in pulmonary capillary wedge pressure, systemic vascular resistance, mean arterial pressure, and heart rate, as well as a decrease in circulating aldosterone and norepinephrine levels, respectively. The occurrence of arterial hypotension in patients with heart failure is 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 achieved statistically significant reductions in systolic and diastolic blood pressure. Blood pressure measurements 24 hours after dosing compared to measurements 5–6 hours after dosing demonstrated that the antihypertensive effect lasts 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). Despite losartan causing a pronounced reduction in blood pressure, it does not significantly affect heart rate.

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

In two large placebo-controlled studies (ONTARGET and NEPHRON-D), the benefits of concomitant use of ACE inhibitors and angiotensin II receptor antagonists were investigated. The studies showed that concomitant use of ACE inhibitors with angiotensin II receptor antagonists in patients with a history of cardiovascular or cerebrovascular diseases or type 2 diabetes with signs of target organ damage did not demonstrate significant positive effects on kidney function and/or cardiovascular system 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 study, 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, and the study was terminated. Cardiovascular death and strokes were more frequent in the aliskiren group than in the placebo group; in addition, adverse events and serious adverse effects such as hyperkalemia, arterial hypotension, and renal dysfunction were also more common in the aliskiren-treated 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 interfere with the tubular reabsorption mechanism of electrolytes in the kidneys, directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and increases aldosterone secretion, leading to a corresponding increase in urinary potassium excretion and bicarbonate loss, as well as an increase in serum potassium concentration. The renin-aldosterone axis is mediated by angiotensin II; therefore, concomitant use of angiotensin II receptor antagonists may prevent potassium loss associated with thiazide diuretic use.

After oral administration, diuresis begins within two hours, reaches a maximum approximately four hours later, 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 hydrochlorothiazide and the development of non-melanoma skin cancer.

One study included a population of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 patients from the control population, respectively. High use of HCTZ (≥50,000 mg cumulative) was associated with an adjusted risk coefficient (RR) of 1.29 (95% confidence interval: 1.23–1.35) for BCC and 3.98 (95% confidence interval: 3.68–4.31) for SCC. A cumulative dose-effect relationship was observed for both BCC and SCC.

Another study showed a possible association between lip cancer (SCC) and hydrochlorothiazide use: 633 patients with lip cancer (SCC) were compared with 63,067 patients from the control population using a random sampling strategy. A cumulative dose-effect relationship was demonstrated with an adjusted RR of 2.1 (95% confidence interval: 1.7–2.6) for overall use, increasing to RR 3.9 (3.0–4.9) for high use (~25,000 mg) and RR 7.7 (5.7–10.5) for 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 the active carboxylic acid metabolite and inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached at approximately 1 hour and 3–4 hours, respectively. When administered with food, no clinically significant effect on the plasma concentration profile of losartan is observed.

Distribution

Losartan

Losartan and its active metabolite are >99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 L. According to study results, losartan may minimally or not at all cross the blood-brain barrier.

Hydrochlorothiazide

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

Biotransformation

Losartan

Approximately 14% of the dose of losartan administered intravenously or orally is converted into the active metabolite. After oral and intravenous administration of radiolabeled 14C-potassium losartan, radioactivity in circulating plasma was primarily associated with the presence of losartan and its active metabolite. In addition to the active metabolite, inactive metabolites are formed, including two major ones formed through 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 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, approximately 4% of the administered dose is excreted unchanged in urine and about 6% as the active metabolite. Pharmacokinetic properties of losartan and its active metabolite are linear following oral administration of losartan at doses up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially, with terminal half-lives of approximately 2 hours and 6–9 hours, respectively. After oral administration of C14-labeled losartan, approximately 35% of radioactivity is found in urine and 58% in feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. When monitoring drug levels in plasma for at least 24 hours, the elimination half-life ranged from 5.6 to 14.8 hours. At least 61% of the administered dose was excreted unchanged within 24 hours.

Patient characteristics

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 statistically significantly differ from those in younger patients with arterial hypertension.

Losartan

In patients with mild to moderate alcoholic cirrhosis of the liver, 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.

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

Contraindications.

• Hypersensitivity to losartan or to any of the components of the medicinal product.
• Hypersensitivity to other drugs derived from sulfonamides (such as hydrochlorothiazide).
• Refractory hypokalemia or hypercalcemia.
• Severe impairment of liver function: cholestasis and disorders associated with biliary obstruction.
• Refractory hyponatremia.
• Symptomatic hyperuricemia/gout.
• Pregnancy and planned pregnancy (see section "Use in pregnancy or breastfeeding").
• Anuria.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Concomitant use of medicinal products containing aliskiren in patients with diabetes or renal impairment (eGFR < 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

According to available reports, rifampicin and fluconazole reduce the level of the active metabolite. The clinical consequences of these interactions have not been studied.

Combination of losartan, as with other agents that block angiotensin II or its effects, with potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium-containing supplements, or potassium salts, or other drugs, such as trimethoprim-containing drugs added to heparin-containing medicinal products, may increase potassium levels. Concomitant use 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 if concomitant use of lithium salts with angiotensin II receptor antagonists is necessary.

When angiotensin II receptor antagonists are prescribed together with NSAIDs (e.g., selective 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, with possible development of acute renal failure and increased serum potassium levels, especially in patients with pre-existing renal impairment at the start of therapy. The above-mentioned combination of drugs should be used with caution in elderly patients. Adequate hydration of patients 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 treatment with non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2, concomitant use of angiotensin II receptor antagonists may lead to further deterioration of renal function. This effect is usually reversible.

Results of 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.

When used concomitantly with drugs such as tricyclic antidepressants, neuroleptics, baclofen, amifostine, whose primary or secondary action is to lower blood pressure, the risk of developing arterial hypotension is increased.

Hydrochlorothiazide:

When used concomitantly with thiazide diuretics, the following interactions may occur:

• alcohol, barbiturates, narcotics, or antidepressants: orthostatic hypotension may occur;
• antidiabetic agents (oral hypoglycemic agents and insulin): thiazide use may affect glucose tolerance, and dose adjustment of the antidiabetic agent may be necessary. 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: enhanced hypotensive effect;
• cholestyramine and colestipol resins: reduced absorption of hydrochlorothiazide due to anion-exchange resins. Single doses of cholestyramine or colestipol resin bind hydrochlorothiazide and reduce its gastrointestinal absorption by approximately 85% and 43%, respectively;
• glucocorticoids, corticotropin, carbenoxolone, amphotericin B: electrolyte imbalance, particularly potassium;
• responses to pressor amines, but insufficient to preclude their use;
• non-depolarizing muscle relaxants (e.g., tubocurarine): possible potentiation of muscle relaxant effect;

• lithium: concomitant administration with lithium-containing products is contraindicated due to reduced lithium excretion and increased risk of lithium intoxication;

• drugs used for 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 necessary. The frequency of hypersensitivity reactions to allopurinol may increase with concomitant use of thiazides;
• anticholinergic drugs (e.g., atropine, biperiden): due to reduced gastrointestinal motility and delayed gastric emptying, bioavailability of thiazide diuretics is increased;
• cytotoxic agents (e.g., cyclophosphamide, methotrexate): thiazides may reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effects;
• salicylates: under the influence of hydrochlorothiazide, high-dose salicylates may have enhanced toxic effects on the central nervous system;
• methyldopa: isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa;
• cyclosporines: concomitant use of cyclosporine may increase the risk of hyperuricemia and complications such as gout;
• cardiac glycosides: hypokalemia or hypomagnesemia caused by thiazide therapy may predispose to cardiac arrhythmias induced by digitalis glycosides;
• medicinal products whose efficacy is influenced by changes in serum potassium levels: periodic monitoring of serum potassium levels and ECG is recommended if losartan/hydrochlorothiazide is used concomitantly with drugs whose efficacy is affected by changes in serum potassium levels (such as cardiac glycosides and antiarrhythmic agents), or with the following drugs that may induce polymorphic ventricular tachycardia of the "torsades de pointes" type (ventricular tachycardia), 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, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinpocetine);
• calcium salts: thiazide diuretics may increase serum calcium levels by reducing its excretion. If calcium-containing dietary supplements are necessary, serum calcium levels should be monitored and adjusted;
• effect on laboratory test results: since thiazides affect calcium metabolism, they may influence assessment of parathyroid gland function;
• carbamazepine: risk of symptomatic hyponatremia. Clinical and biological monitoring should be performed;
• iodinated contrast agents: in cases of diuretic-induced dehydration, the risk of acute renal failure increases, especially with high doses of iodinated agents. The patient's fluid volume should be restored before administration of such agents;
• amphotericin B (for parenteral use), stimulant laxatives, or glycyrrhizin (from licorice root): hydrochlorothiazide may disturb electrolyte balance, particularly causing hypokalemia;
• 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 (facial, lip, pharyngeal and/or lingual swelling) must be under close supervision (see section "Adverse reactions").

Arterial hypotension and reduced intravascular volume

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

Electrolyte imbalance

Electrolyte imbalance is common in patients with renal impairment, 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 drugs that may increase serum potassium levels (e.g., trimethoprim-containing products) with losartan/hydrochlorothiazide is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment

Due to pharmacokinetic data indicating a significant increase in plasma concentration of losartan in patients with liver 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

There have been reports that in some patients receiving the drug, inhibition of the renin-angiotensin system (RAS) has led to changes in renal function, including renal failure, particularly in patients whose renal function depends on RAS activity, such as those with severe heart failure or pre-existing renal dysfunction. Other agents affecting the RAS may increase blood urea and creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Adverse effects have been observed during losartan therapy; these renal function changes may be reversible and resolve upon discontinuation of treatment. 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

Antihypertensive agents acting via RAS inhibition are generally ineffective in patients with primary hyperaldosteronism. Therefore, losartan potassium/hydrochlorothiazide tablets are not recommended for such patients.

Ischemic heart disease and cerebrovascular disorders

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

Heart failure

In patients with heart failure (with or without concomitant renal impairment), as with other drugs acting on the RAS, 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 to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Ethnic characteristics

It is known that angiotensin-converting enzyme inhibitors, losartan, and other angiotensin antagonists are less effective in lowering blood pressure in black patients compared to other ethnic groups. This is likely due to the predominance of low-renin hypertension among black patients.

Pregnancy

Angiotensin II receptor antagonists (ARBs) are contraindicated as initial therapy during pregnancy. 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, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or lactation").

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 the 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-electrolyte balance, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hydrochlorothiazide

Arterial hypotension and fluid-electrolyte imbalance

As with any antihypertensive agents, symptomatic arterial hypotension may occur in some patients. Patients should be monitored for early detection of clinical signs of fluid-electrolyte imbalance, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may develop during intercurrent diarrhea or vomiting. Such patients require monitoring of serum electrolyte levels. In hot weather, hyponatremia due to dilution may occur in patients with edema.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In some cases, adjustment of the dose 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 apparent during thiazide treatment.

Thiazides may reduce calcium excretion in urine 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 be associated with thiazide diuretic therapy.

In such patients, the use of thiazide diuretics may lead to hyperuricemia and/or development of gout. Since losartan reduces uric acid levels, its combination with hydrochlorothiazide reduces the hyperuricemic effect caused by the diuretic.

Hepatic impairment

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

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

Other effects

Hypersensitivity reactions may occur in patients receiving thiazide diuretics, even in the absence of a history of allergy or bronchial asthma. There have been reports of exacerbation or progression of systemic lupus erythematosus during thiazide diuretic therapy (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

Patients with rare hereditary galactose intolerance, lactose intolerance, or glucose-galactose malabsorption should not take this medicine (see section "Composition").

Non-melanoma skin cancer

Two epidemiological studies have reported an increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) with high cumulative doses of hydrochlorothiazide. The possible mechanism may be the photosensitizing effect of hydrochlorothiazide.

Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of non-melanoma skin cancer and advised to regularly check their skin for new lesions or changes in existing ones and to report any suspicious skin lesions to their physician. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsies.

Patients should be advised to limit exposure to sunlight and UV radiation and, when exposure is unavoidable, to use appropriate skin protection to minimize the risk of skin cancer.

The use of hydrochlorothiazide should also be carefully reconsidered in patients with a history of skin cancer (see section "Adverse reactions").

Use during pregnancy or lactation.

Pregnancy

Angiotensin II receptor antagonists

The use of angiotensin II receptor antagonists is contraindicated during pregnancy (see sections "Contraindications" and "Special precautions for use"). Epidemiological data on the teratogenic risk of angiotensin II receptor antagonists during the first trimester of pregnancy are insufficient and do not exclude an increased teratogenic risk. Women planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. If pregnancy occurs, treatment with angiotensin II receptor antagonists should be discontinued immediately and, if necessary, alternative therapy initiated. It has been established that the use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy increases fetal toxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If angiotensin II receptor antagonists were used from the second trimester of pregnancy, ultrasound assessment of renal function and skull ossification in the newborn should be performed.

Newborns whose mothers received angiotensin II receptor antagonists during pregnancy must be closely monitored due to the risk of arterial hypotension (see section "Special precautions for use").

Hydrochlorothiazide

Experience with the use of hydrochlorothiazide during pregnancy is limited, especially 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, the use of hydrochlorothiazide during the second and third trimesters of pregnancy may negatively affect fetoplacental perfusion and lead to disorders in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.

Hydrochlorothiazide should not be used for the treatment of edema in 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 the course of the disease. Hydrochlorothiazide should not be used for the treatment of essential hypertension in pregnant women.

Lactation period

Angiotensin II receptor antagonists (ARBs)

There is no information on the use of Presartan® H-50 during lactation; therefore, the drug is not recommended during this period. An alternative agent with a more established safety profile during lactation should be selected, especially for newborns and preterm infants.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human breast milk in small amounts. High doses of thiazides, causing increased diuresis, may suppress breast milk secretion. The use of Presartan® H-50 during lactation is not recommended. If Presartan® H-50 is used during this period, the dose should be as low as possible.

Ability to affect reaction speed 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 plan to drive or operate machinery should be aware that dizziness or somnolence may occasionally occur during antihypertensive therapy, particularly at the beginning of treatment and when increasing the dose.

Method of Administration and Dosage

Presartan® H-50 may be administered in combination with other antihypertensive agents. Presartan® H-50 may be taken regardless of food intake.

Arterial Hypertension

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

The usual initial maintenance dose is 1 tablet of Presartan® H-50 once daily. For patients who do not achieve adequate therapeutic response after 2–4 weeks of treatment with 1 tablet of Presartan® H-50 (50 mg losartan/12.5 mg hydrochlorothiazide), the dose may be increased to 2 tablets of Presartan® H-50 50/12.5 mg once daily. The maximum dose is 2 tablets of Presartan® H-50 50/12.5 mg once daily. The antihypertensive effect is generally achieved within 3–4 weeks after initiation of therapy.

No initial dose adjustment of Presartan® H-50 is required for elderly patients. However, Presartan® H-50 at a dose of 2 tablets of 50/12.5 mg should not be used as initial therapy in elderly patients.

Use in Patients with Renal Impairment and Patients on Hemodialysis

No initial dose adjustment is required for patients with mild to moderate renal impairment (i.e., creatinine clearance of 30–50 mL/min). Tablets containing losartan and hydrochlorothiazide are not recommended for patients on hemodialysis. The use of the drug 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 therapy.

Use in Patients with Hepatic Impairment

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

Use in Elderly Patients

Generally, administration of the drug in elderly patients does not require dose adjustment.

Children

The efficacy and safety of the drug for use in children have not been established; therefore, the use of the drug in children is contraindicated.

Overdose

There are no data on specific treatment for overdose with Presartan® H-50. Treatment is symptomatic and supportive. In case of overdose, therapy with Presartan® H-50 should be discontinued and the patient should be monitored. Possible therapeutic measures include induction of emesis if the drug has been recently ingested, as well as correction of dehydration, electrolyte imbalances, hepatic coma, and arterial hypotension using symptomatic therapy.

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 cannot be 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 receiving cardiac glycosides, hypokalemia may predispose to arrhythmias. Hydrochlorothiazide is eliminated by hemodialysis, although the extent of removal has not been established.

Adverse Reactions

The adverse reactions listed below are categorized by "System Organ Class" and frequency of occurrence, defined as follows: 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. Adverse events were limited to those previously reported with the use of losartan and/or hydrochlorothiazide alone.

In controlled clinical trials in patients with primary arterial hypertension, dizziness was the only treatment-related adverse reaction that occurred at a rate exceeding placebo by 1% or more among patients receiving losartan and hydrochlorothiazide. During post-marketing use of the drug, the following adverse reactions have been reported for potassium losartan/hydrochlorothiazide.

Hepatobiliary disorders: rare – hepatitis.

Investigations: rare – hyperkalaemia, increased alanine aminotransferase (ALT) levels.

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

Adverse reactions associated with losartan

The following adverse reactions have been reported during clinical trials and post-approval use of losartan.

Blood and lymphatic system disorders: uncommon – anaemia, Schönlein-Henoch purpura, ecchymosis, haemolysis; frequency not known – thrombocytopenia.

Cardiac disorders: 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).

Ear and labyrinth disorders: uncommon – vertigo, sensation of ringing/noise in the ears.

Eye disorders: uncommon – blurred vision, burning/tingling sensation in the eyes, conjunctivitis, decreased visual acuity.

Gastrointestinal disorders: common – abdominal pain, nausea, vomiting, diarrhoea, dyspepsia; uncommon – toothache, constipation, dry mouth, flatulence, gastritis, vomiting, intestinal obstruction; frequency not known – pancreatitis.

General disorders and administration site conditions: common – asthenia, increased fatigue, chest pain; uncommon – facial swelling, oedema, increased body temperature; frequency not known – influenza-like symptoms, malaise.

Hepatobiliary disorders: frequency not known – liver function test abnormalities.

Immune system disorders: rare – hypersensitivity reactions: anaphylactic reactions, angioedema, laryngeal and vocal cord oedema leading to airway obstruction, and/or oedema of the face, lips, pharynx, and/or tongue. Angioedema has been previously reported in some of these patients with other medicinal products, including ACE inhibitors.

Metabolism and nutrition disorders: uncommon – loss of appetite, gout.

Musculoskeletal and connective tissue disorders: common – muscle spasms, back pain, leg pain, myalgia; uncommon – arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, hip joint pain, fibromyalgia, muscle weakness; frequency not known – rhabdomyolysis.

Nervous system disorders: common – headache, dizziness; uncommon – restlessness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope; frequency not known – dysgeusia.

Psychiatric disorders: common – insomnia; uncommon – anxiety, anxiety disorder, panic disorder, confusion, depression, unusual dreams, sleep disturbances, somnolence, memory impairment.

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.

Respiratory, thoracic and mediastinal disorders: common – cough, upper respiratory tract infections, nasal congestion, sinusitis, sinus disorders; uncommon – throat discomfort, pharyngitis, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion and pulmonary congestion.

Skin and subcutaneous tissue disorders: uncommon – alopecia, dermatitis, dry skin, erythema, skin redness, photosensitivity, pruritus, rash, urticaria, hyperhidrosis.

Vascular disorders: uncommon – vasculitis; frequency not known – dose-dependent orthostatic effects.

Investigations: common – hyperkalaemia, slight decrease in haematocrit and haemoglobin levels, hypoglycaemia; uncommon – slight increase in serum urea and creatinine levels; very rare – increased levels of liver enzymes and bilirubin; frequency not known – hyponatraemia.

Adverse reactions associated with hydrochlorothiazide

Blood and lymphatic system disorders: uncommon – agranulocytosis, aplastic anaemia, haemolytic anaemia, leukopenia, purpura, thrombocytopenia, neutropenia.

Immune system disorders: rare – anaphylactic reactions, anaphylactic shock.

M metabolism and nutrition disorders: uncommon – loss of appetite, anorexia, hyperglycaemia, bone marrow suppression, hyperuricaemia, hypomagnesaemia, hypokalaemia, hyponatraemia, hypercalcaemia; with high-dose use, possible increase in blood lipid levels.

Psychiatric disorders: uncommon – insomnia.

Nervous system disorders: common – cephalalgia (headache).

Eye disorders: uncommon – transient blurred vision, xanthopsia; frequency not known – acute myopia, secondary acute angle-closure glaucoma.

Vascular disorders: uncommon – necrotizing vasculitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: uncommon – respiratory distress, including pneumonitis and pulmonary oedema.

Gastrointestinal disorders: uncommon – sialadenitis, dry mouth, spasms, gastric mucosal irritation, nausea, vomiting, diarrhoea, constipation.

Hepatobiliary disorders: uncommon – jaundice (intrahepatic cholestasis), cholecystitis, pancreatitis, hypochloraemic alkalosis, which may precipitate hepatic encephalopathy or hepatic coma.

Skin and subcutaneous tissue disorders: uncommon – photosensitivity, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome; frequency not known – cutaneous lupus erythematosus, non-melanoma skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)).

Epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide and the development of non-melanoma skin cancer (see also sections "Pharmacodynamics" and "Special precautions for use").

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms, cramps.

Renal and urinary disorders: uncommon – glucosuria, interstitial nephritis, renal dysfunction, renal failure, decreased glucose tolerance.

Reproductive system disorders: erectile dysfunction/impotence.

General disorders and administration site conditions: uncommon – increased body temperature, hot flushes, dizziness.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging.

14 tablets in a blister; 2 blisters in a cardboard carton.

10 tablets in a blister; 3 blisters in a cardboard carton.

Prescription category. Prescription only.

Manufacturer.

Ipca Laboratories Limited, India / Ipca Laboratories, Limited, India

Manufacturer's address and place of business.

Plot No. 255/1, Village – Atal, U.T. Dadra and Nagar Haveli, 396 230 Silvassa, India.