Lozap^® Plus (Tablets) Instructions for Use

ATC Code

C09DA01 (Losartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Losartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined antihypertensive drug (diuretic + angiotensin II receptor antagonist)

Pharmacotherapeutic Group

Antihypertensive combination agent (diuretic + angiotensin II receptor antagonist)

Pharmacological Action

A combined drug that has an antihypertensive effect. It contains Losartan potassium – an angiotensin II receptor antagonist (subtype AT₁) (ARB II) and Hydrochlorothiazide – a thiazide diuretic.

Hydrochlorothiazide + Losartan

Losartan and Hydrochlorothiazide demonstrate a synergistic antihypertensive effect, reducing blood pressure to a greater extent than each component separately. It is assumed that this effect is the result of the additive action of both components.

Furthermore, as a result of the diuretic action of Hydrochlorothiazide, plasma renin activity increases, aldosterone secretion increases, plasma potassium concentration decreases, and angiotensin II levels increase.

The use of losartan blocks all physiologically significant actions of angiotensin II and reduces potassium loss associated with the use of the diuretic by inhibiting aldosterone.

Losartan has a mild and short-term uricosuric effect. Hydrochlorothiazide leads to a moderate increase in plasma uric acid levels; the combination of losartan and hydrochlorothiazide helps to attenuate diuretic-induced hyperuricemia.

The antihypertensive effect of the Hydrochlorothiazide + losartan combination is maintained for 24 hours. In clinical studies lasting at least one year, the antihypertensive effect was maintained during ongoing therapy.

Despite a significant reduction in blood pressure, taking the Hydrochlorothiazide + losartan combination does not have a significant clinical effect on heart rate.

Clinical studies have shown that after 12 weeks of therapy with the combination of losartan 50 mg/hydrochlorothiazide 12.5 mg, the minimum diastolic blood pressure (sitting measurement) decreased by an average of 13.2 mm Hg.

The Hydrochlorothiazide + losartan combination effectively reduces blood pressure in men and women, patients of Black African, as well as other races, in young (<65 years) and elderly (≥65 years) patients and in any degree of arterial hypertension.

Hydrochlorothiazide

The mechanism of action of thiazide diuretics (thiazides) is not fully understood. Thiazides block the reabsorption of sodium and chloride ions in the early part of the renal tubules.

Thus, they increase the excretion of sodium and chloride and, consequently, the removal of water from the body.

As a result of the diuretic action of hydrochlorothiazide, the volume of circulating fluid decreases, leading to an increase in renin activity and plasma aldosterone levels.

This leads to increased excretion of potassium ions in the urine and a decrease in blood potassium levels (hypokalemia). Hydrochlorothiazide also increases the excretion of magnesium ions and decreases the excretion of calcium ions in the urine.

Thiazide diuretics reduce the renal excretion of uric acid and increase its level in the blood.

Thiazide diuretics also reduce carbonic anhydrase activity by enhancing the excretion of bicarbonate ions.

But this effect is usually mild and does not affect urine pH.

At maximum therapeutic doses, the diuretic/natriuretic effect of all thiazide diuretics is approximately the same. Natriuresis and diuresis occur within 2 hours and reach their maximum approximately 4 hours later.

The duration of the diuretic effect of hydrochlorothiazide is from 6 to 12 hours. Hydrochlorothiazide has an antihypertensive effect. Thiazide diuretics do not affect normal blood pressure.

Losartan

Losartan is a synthetic angiotensin II receptor blocker (type AT₁). Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the RAAS and a key factor in the pathophysiology of arterial hypertension.

Angiotensin II binds to AT₁ receptors located in many tissues (in vascular smooth muscle, adrenal glands, kidneys, and heart) and causes a number of biologically important effects, including vasoconstriction and aldosterone release.

Angiotensin II also stimulates the proliferation of smooth muscle cells.

Losartan selectively blocks AT₁ receptors. Losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically significant effects of angiotensin II in vitro and in vivo, regardless of the source and pathway of its synthesis.

Losartan has no agonistic activity and does not block receptors for other hormones or ion channels that play an important role in regulating the function of the cardiovascular system.

Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that breaks down bradykinin. Consequently, there is no potentiation of undesirable effects mediated by bradykinin.

When losartan is used, the elimination of the negative feedback of angiotensin II on renin secretion leads to an increase in its plasma activity. The increase in renin activity leads to an increase in plasma angiotensin II concentration.

Despite this increase, the antihypertensive effect and the reduction in 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 within 3 days.

Both losartan and its primary active metabolite have a greater affinity for AT₁ receptors than for AT₂ receptors. The specified metabolite is 10-40 times more active than losartan.

The incidence of cough is comparable in patients taking losartan or Hydrochlorothiazide and is significantly lower than with the use of ACE inhibitors.

In patients with arterial hypertension, proteinuria without diabetes mellitus and taking losartan, a significant reduction in proteinuria, fractional excretion of proteins and immunoglobulin G was noted.

Losartan stabilizes the glomerular filtration rate (GFR) and reduces the filtration fraction. In general, losartan causes a decrease in serum uric acid levels (usually <0.4 mg/dl), which persists during long-term therapy.

Losartan does not affect autonomic reflexes and does not have a long-term effect on plasma norepinephrine levels.

In patients with left ventricular failure, losartan at doses of 25 mg and 50 mg has a positive hemodynamic and neurohumoral effect, characterized by an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, systemic vascular resistance, systemic blood pressure and heart rate, as well as plasma aldosterone and norepinephrine concentrations, respectively.

The development of arterial hypotension in such patients with heart failure was dose-dependent.

Pharmacokinetics

Hydrochlorothiazide

Absorption and Distribution

Hydrochlorothiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. After oral administration of a 100 mg dose, the C_max of hydrochlorothiazide in plasma is reached in 1.5-2.5 hours.

At the peak of diuretic activity (approximately 4 hours after administration), the plasma concentration of hydrochlorothiazide is 2 mcg/ml. Plasma protein binding is 40%.

Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk; it does not cross the blood-brain barrier.

Metabolism

Hydrochlorothiazide is not metabolized in the human body.

Excretion

The primary route of excretion is through the kidneys (filtration and secretion) unchanged. Approximately 61% of the orally administered dose is excreted within 24 hours.

In patients with normal renal function, T_1/2 ranges from 5.6 to 14.8 hours (average 6.4 hours).

Pharmacokinetics in Special Clinical Situations

Renal impairment: In patients with moderate renal impairment, the T_1/2 of hydrochlorothiazide averages 11.5 hours, and in patients with CrCl less than 30 ml/min – 20.7 hours.

Losartan

Absorption

Losartan is well absorbed after oral administration and undergoes presystemic metabolism to form an active carboxylic acid metabolite, as well as other inactive metabolites.

The systemic bioavailability of losartan in tablet form is approximately 33%. Mean C_max of losartan and its active metabolite are achieved at 1 and 3-4 hours, respectively.

When losartan was taken concurrently with a standardized meal, no clinically significant effect on the plasma concentration profile of the drug was observed.

Distribution

Losartan and its active metabolite are more than 99% bound to plasma proteins, primarily albumin. The V_d of losartan is 34 L. Studies have shown that losartan poorly penetrates or does not penetrate the blood-brain barrier.

Metabolism

Approximately 14% of the losartan dose administered intravenously or orally is converted to its active metabolite. After intravenous and oral administration of ¹⁴C-labeled losartan potassium, the radioactivity in circulating plasma is due mainly to losartan and its active metabolite.

Minimal conversion of losartan to its active metabolite was observed in approximately 1% of study participants. In addition to the active metabolite, inactive metabolites are formed, including 2 main metabolites formed by hydroxylation of the butyl side chain and a minor metabolite – N-2-tetrazole glucuronide.

Excretion

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 approximately 74 ml/min and 26 ml/min, respectively.

After oral administration, about 4% of the losartan dose is excreted unchanged by the kidneys and about 6% of the dose is excreted by the kidneys as the active metabolite.

The pharmacokinetics of losartan and its active metabolite are linear when losartan is administered orally in doses up to 200 mg/day.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal T_1/2 of about 2 and 6-9 hours, respectively.

Losartan and its active metabolite are excreted via the intestine and kidneys. After oral administration of ¹⁴C-labeled losartan, approximately 35% of the radioactivity is excreted in the urine and 58% in the feces.

Pharmacokinetics in Special Clinical Situations

Gender. Plasma concentrations of losartan in women with hypertension were twice the corresponding values in men with hypertension. Concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference, however, is of no clinical significance.

Patients with hepatic impairment. In patients with mild to moderate alcoholic liver cirrhosis (< 9 points on the Child-Pugh scale) after oral administration, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young male patients.

Patients with renal impairment. Plasma concentrations of losartan in patients with CrCl above 10 ml/min did not differ from those in patients with normal renal function. The AUC of losartan in patients on hemodialysis was approximately 2 times greater compared to the AUC of losartan in patients with normal renal function.

Plasma concentrations of the active metabolite did not change in patients with renal impairment or patients on hemodialysis. Losartan and its active metabolite are not removed by the hemodialysis procedure.

Ethnicity. Pharmacokinetic studies showed no differences in AUC in patients of Japanese ethnicity and other patients, but the AUC of the E-3174 metabolite was 1.5 times higher in patients of Japanese ethnicity compared to other patients. The clinical significance of these results has not been established.

Losartan/Hydrochlorothiazide

Pharmacokinetics in Special Clinical Situations

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

Indications

• Arterial hypertension (in patients for whom combination therapy is optimal);
• Reduction of the risk of cardiovascular diseases and mortality in patients with arterial hypertension and left ventricular hypertrophy, manifested by a combined reduction in the frequency of cardiovascular mortality, the frequency of stroke and myocardial infarction.

ICD codes

Dosage Regimen

Tablets

Orally, regardless of meals.

Arterial hypertension

The drug Lozap^® Plus is intended for the treatment of patients with arterial hypertension for whom combination therapy with Losartan and Hydrochlorothiazide is indicated.

Initial dose of the drug – 50 mg+12.5 mg (1 tablet) once a day (it is necessary to use 1 tablet of another drug containing Losartan + Hydrochlorothiazide in the specified dosage).

For patients in whom adequate blood pressure control is not achieved with the drug at a dosage of 50 mg+12.5 mg, the dose of the drug can be increased to 1 tablet of Lozap^® Plus 100 mg+12.5 mg once a day or 1 tablet of Lozap^® Plus 100 mg+25 mg once a day.

Lozap^® Plus 100 mg+12.5 mg can be prescribed to patients with arterial hypertension in whom adequate blood pressure control is not achieved with losartan at a dosage of 100 mg.

Maximum dose – 1 tablet of Lozap^® Plus 100 mg+25 mg once a day.

The maximum antihypertensive effect is achieved within 3-4 weeks after starting treatment.

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

Initial dose – 100 mg+12.5 mg (1 tablet) once a day, if target blood pressure values are not achieved while taking 1 tablet of 50 mg+12.5 mg (another drug containing Losartan + Hydrochlorothiazide in the specified dosage). If necessary, the dose can be increased to 100 mg+25 mg (1 tablet) once a day.

In moderate renal impairment (CrCl 30-50 ml/min) no adjustment of the initial dose is required. In severe renal impairment (CrCl less than 30 ml/min) the use of the drug is contraindicated. The use of the drug is not recommended for patients on hemodialysis.

The use of the drug is contraindicated in patients with severe hepatic impairment (>9 points on the Child-Pugh scale).

In patients with reduced blood volume it is necessary to correct blood volume and/or plasma sodium levels before starting the drug.

For elderly patients (over 65 years old) no dose adjustment is required.

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Adverse Reactions

The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), frequency unknown (cannot be estimated from the available data).

In clinical studies with losartan/hydrochlorothiazide, no adverse reactions specific to the drug combination were observed. Adverse reactions are limited to those previously observed with the use of losartan and/or hydrochlorothiazide separately.

In controlled clinical studies for the treatment of essential hypertension in patients receiving losartan and Hydrochlorothiazide, the only adverse reaction that occurred with a frequency of 1% or more compared to placebo was dizziness.

In addition, there are other adverse reactions that have been reported during the use of the losartan/Hydrochlorothiazide combination (Table 1).

Table 1. Adverse reactions reported with the combination of hydrochlorothiazide and losartan and with hydrochlorothiazide monotherapy or losartan monotherapy

Contraindications

• Hypersensitivity to any component of the drug or to other sulfonamide-derived drugs;
• Refractory hypokalemia or hypercalcemia;
• Severe hepatic impairment (>9 points on the Child-Pugh scale);
• Refractory hyponatremia;
• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Anuria;
• Concomitant use with drugs containing aliskiren in patients with diabetes mellitus and patients with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established).

With caution

• Bilateral renal artery stenosis or stenosis of the artery to a single kidney;
• Hyperkalemia;
• Post-kidney transplant status (no experience of use);
• Aortic or mitral stenosis;
• Hypertrophic obstructive cardiomyopathy;
• Chronic heart failure with concomitant severe renal impairment;
• Severe heart failure (NYHA functional class IV);
• Chronic heart failure with life-threatening arrhythmias;
• Coronary artery disease;
• Cerebrovascular diseases;
• Primary hyperaldosteronism;
• History of angioedema;
• Arterial hypotension;
• Hepatic impairment;
• Renal impairment;
• Water-electrolyte imbalance;
• Patients with reduced blood volume (e.g., those receiving high-dose diuretic therapy) due to the possibility of symptomatic arterial hypotension;
• Hypokalemia;
• Hyponatremia;
• Hypercalcemia;
• Increased QT interval on ECG;
• Concomitant use of drugs that can cause polymorphic ventricular tachycardia of the "torsades de pointes" type or increase the QT interval on ECG;
• Concomitant use of drugs that can cause hypokalemia, cardiac glycosides;
• History of allergic reactions to penicillin;
• Hyperparathyroidism;
• Hyperuricemia, gout, history of non-melanoma skin cancer (see section "Special Precautions").

Use in Pregnancy and Lactation

Hydrochlorothiazide

Use in pregnancy

There is limited experience with hydrochlorothiazide use during pregnancy (especially in the first trimester). Preclinical safety data are insufficient.

Hydrochlorothiazide crosses the placental barrier and is detected in cord blood. Considering the mechanism of pharmacological action of hydrochlorothiazide, its use in the second and third trimesters of pregnancy may impair fetoplacental perfusion and lead to complications in the fetus and newborn such as jaundice, water-electrolyte imbalance, and thrombocytopenia. Cases of thrombocytopenia in newborns whose mothers received thiazide diuretics have been described.

Use of hydrochlorothiazide during pregnancy is contraindicated. Hydrochlorothiazide should not be used to treat late pregnancy complications (edema, arterial hypertension, or preeclampsia), as it increases the risk of decreased blood volume and placental hypoperfusion but does not have a favorable effect on the course of these pregnancy complications. Diuretics do not prevent the development of preeclampsia.

Breastfeeding period

Hydrochlorothiazide passes into breast milk, therefore use of the drug during breastfeeding is contraindicated.

If hydrochlorothiazide use during lactation is absolutely necessary, breastfeeding should be discontinued.

Angiotensin II receptor antagonists

Use in pregnancy

Use of angiotensin II receptor antagonists during pregnancy is contraindicated.

Epidemiological data on the risk of teratogenic effects of ACE inhibitors in the first trimester of pregnancy are not sufficiently convincing, but the risk to the fetus cannot be completely ruled out. Although controlled epidemiological studies with ARBs have not been conducted, similar risks may be characteristic for this class of drugs.

Patients planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile. If pregnancy is confirmed, ARB use should be discontinued immediately and alternative treatment initiated if necessary.

It is known that the use of ARBs in the second and third trimesters of pregnancy has toxic effects on the fetus (decreased renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalemia).

If ARBs are used in the second or third trimester of pregnancy, ultrasound examination of the fetus is recommended to monitor renal function and skull condition.

Children whose mothers took ARBs during pregnancy should be closely monitored for the development of arterial hypotension.

Breastfeeding period

Due to the lack of sufficient safety information, the use of ARBs during breastfeeding is contraindicated. During breastfeeding, preference should be given to alternative treatment with an established safety profile.

Use in Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment.

Use with caution in patients with hepatic impairment or progressive liver diseases.

Use in Renal Impairment

In moderate renal failure (creatinine clearance 30-50 ml/min), initial dose adjustment is not required. In severe renal failure (creatinine clearance less than 30 ml/min), use of the drug is contraindicated.

Use with caution after kidney transplantation (no experience of use), in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney.

Pediatric Use

The drug is contraindicated in children and adolescents under 18 years of age (efficacy and safety not established).

Geriatric Use

Use with caution in patients over 75 years of age.

Special Precautions

Hydrochlorothiazide

Renal impairment

In patients with renal impairment, Hydrochlorothiazide may cause azotemia. In renal failure, accumulation of hydrochlorothiazide is possible.

In patients with reduced renal function, periodic monitoring of creatinine clearance is necessary. If renal function impairment progresses and/or oliguria (anuria) occurs, Hydrochlorothiazide should be discontinued.

Hepatic impairment

When using thiazide diuretics in patients with hepatic impairment, hepatic encephalopathy may develop. The use of thiazides is contraindicated in patients with severe hepatic insufficiency or hepatic encephalopathy. In patients with mild to moderate hepatic insufficiency and/or progressive liver diseases, Hydrochlorothiazide should be used with caution, since even a slight change in water-electrolyte balance and accumulation of ammonium in the blood serum can cause hepatic coma. If symptoms of encephalopathy appear, diuretic use should be discontinued immediately.

Water-electrolyte balance and metabolic disorders

Thiazide diuretics (including Hydrochlorothiazide) can cause decreased blood volume (hypovolemia) and water-electrolyte imbalance (including hypokalemia, hyponatremia, hypochloremic alkalosis). Clinical symptoms of water-electrolyte imbalance are dry mouth, thirst, weakness, lethargy, fatigue, drowsiness, restlessness, muscle pain or cramps, muscle weakness, marked blood pressure decrease, oliguria, tachycardia, arrhythmia, and gastrointestinal disorders (such as nausea and vomiting). In patients receiving hydrochlorothiazide therapy (especially during long-term course treatment), clinical symptoms of water-electrolyte imbalance should be identified and electrolyte levels in the blood should be regularly monitored.

Sodium

All diuretic drugs can cause hyponatremia, sometimes leading to serious complications. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. Concomitant decrease in chloride ions can lead to secondary compensatory metabolic alkalosis, but the frequency and severity of this effect are insignificant. It is recommended to determine plasma sodium levels before starting treatment and regularly monitor this parameter during hydrochlorothiazide administration.

Potassium

When using thiazide and thiazide-like diuretics, there is a risk of a sharp decrease in plasma potassium levels and the development of hypokalemia (potassium concentration less than 3.4 mmol/l). Hypokalemia increases the risk of cardiac rhythm disturbances (including severe arrhythmias) and enhances the toxic effect of cardiac glycosides. Furthermore, hypokalemia (as well as bradycardia) is a condition that contributes to the development of polymorphic ventricular tachycardia of the "torsades de pointes" type, which can be fatal.

Hypokalemia is most dangerous for the following patient groups: elderly persons, patients simultaneously receiving therapy with antiarrhythmic and non-antiarrhythmic drugs that can cause polymorphic ventricular tachycardia of the "torsades de pointes" type or increase the QT interval on ECG, patients with hepatic impairment, coronary artery disease, chronic heart failure. Additionally, patients with an increased QT interval are at increased risk. It does not matter whether this increase is due to congenital causes or drug effects.

In all the cases described above, it is necessary to avoid the risk of hypokalemia and regularly monitor plasma potassium levels. The first measurement of blood potassium ions should be performed within the first week of starting treatment. If hypokalemia occurs, appropriate treatment should be prescribed. Hypokalemia can be corrected by using potassium-containing drugs or eating foods rich in potassium (dried fruits, fruits, vegetables).

Calcium

Thiazide diuretics can reduce the renal excretion of calcium ions, leading to a slight and temporary increase in plasma calcium levels. In some patients with long-term use of thiazide diuretics, pathological changes in the parathyroid glands with hypercalcemia and hyperphosphatemia have been observed, but without typical complications of hyperparathyroidism (nephrolithiasis, decreased bone mineral density, peptic ulcer). Severe hypercalcemia may be a manifestation of previously undiagnosed hyperparathyroidism.

Due to their effect on calcium metabolism, thiazides can affect laboratory parameters of parathyroid function. Thiazide diuretics (including Hydrochlorothiazide) should be discontinued before testing parathyroid function.

Magnesium

Thiazides have been found to increase renal excretion of magnesium, which can lead to hypomagnesemia. The clinical significance of hypomagnesemia remains unclear.

Glucose

Treatment with thiazide diuretics may impair glucose tolerance. When using hydrochlorothiazide in patients with manifest or latent diabetes mellitus, blood glucose concentration should be regularly monitored. Dose adjustment of hypoglycemic drugs may be required.

Uric acid

In patients with gout, the frequency of attacks may increase or the course of gout may worsen. Close monitoring of patients with gout and impaired uric acid metabolism (hyperuricemia) is necessary.

Lipids

When using hydrochlorothiazide, the concentration of cholesterol and triglycerides in blood plasma may increase.

Acute myopia/secondary angle-closure glaucoma

Hydrochlorothiazide can cause an idiosyncratic reaction leading to the development of acute myopia and an acute attack of secondary angle-closure glaucoma. Symptoms include: sudden decrease in visual acuity or eye pain, which usually occur within several hours or weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to irreversible vision loss. If symptoms appear, hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma are: history of allergic reaction to sulfonamides or penicillin.

Immune system disorders

There are reports that thiazide diuretics (including Hydrochlorothiazide) can cause exacerbation or progression of systemic lupus erythematosus, as well as lupus-like reactions.

In patients receiving thiazide diuretics, hypersensitivity reactions may occur even in the absence of a history of allergic reactions or bronchial asthma.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretic use. If photosensitivity occurs during hydrochlorothiazide administration, treatment should be discontinued.

Non-melanoma skin cancer and lip cancer

In the course of two epidemiological studies based on the Danish National Cancer Registries, an increased risk of non-melanoma skin cancer and lip cancer (basal cell carcinoma and squamous cell carcinoma) was recorded with increasing cumulative dose of hydrochlorothiazide.

Hydrochlorothiazide has a photosensitizing effect, which may be the cause of non-melanoma skin cancer and lip cancer.

Patients taking Hydrochlorothiazide should be informed about the risk of developing non-melanoma skin cancer and lip cancer and the need for regular skin examination for the appearance of new changes, as well as changes in existing ones. If any suspicious skin lesions are detected, the patient should immediately consult a doctor. Particular attention should be paid to patients who have known risk factors for skin cancer, including: skin phototypes I and II (fair and light skin), a family history of skin cancer, a history of skin damage caused by solar or ultraviolet radiation and radiation therapy, smoking, and taking drugs with a photosensitizing effect. Patients should be advised to take measures to prevent the development of skin cancer, such as limiting time spent in the sun and under ultraviolet radiation, as well as using appropriate sun protection when in the sun. Any suspicious skin lesions should be promptly investigated, including histological examination of material obtained by tissue biopsy at the site of the lesion. It may also be necessary to reconsider the justification for the use of hydrochlorothiazide in patients who have previously had non-melanoma skin cancer and lip cancer.

Athletes

Hydrochlorothiazide may give a positive result during doping control in athletes.

Other

Hydrochlorothiazide should be used with particular caution in patients with severe atherosclerosis of the cerebral and coronary arteries.

Thiazide diuretics may reduce the amount of iodine bound to plasma proteins without showing signs of thyroid dysfunction.

Data from epidemiological studies

Two epidemiological studies based on the Danish National Cancer Registries revealed a relationship between hydrochlorothiazide intake and the risk of developing non-melanoma skin cancer and lip cancer (basal cell carcinoma and squamous cell carcinoma). In one study, the use of hydrochlorothiazide in high doses (cumulative dose ≥50000 mg) was associated with the development of basal cell carcinoma and squamous cell carcinoma. Another study observed a possible association between the risk of lip cancer and the use of hydrochlorothiazide. A clear dose-response relationship was observed for patients who received at least one dose, for patients who received a high dose (≥25000 mg), and for patients who received the maximum cumulative dose (≥100000 mg).

Losartan

Angioedema

Patients with a history of angioedema (including edema of the larynx and vocal folds with the development of airway obstruction and/or edema of the face, lips, pharynx, and/or tongue) require careful monitoring of the drug use.

Arterial hypotension and decreased blood volume

In patients with hypovolemia and/or reduced sodium content resulting from intensive use of diuretics, dietary salt restriction, diarrhea, or vomiting, symptomatic arterial hypotension may develop (especially after the first dose). Such conditions should be corrected before starting losartan.

Water-electrolyte balance disorders

Water-electrolyte balance disorders often occur in patients with impaired renal function (with or without diabetes), so plasma potassium levels and creatinine clearance should be carefully monitored, especially carefully in patients with heart failure and creatinine clearance of 30-50 ml/min. The simultaneous use of losartan with potassium-sparing diuretics, potassium preparations, and potassium-containing salt substitutes is not recommended.

Liver dysfunction

Pharmacokinetic data indicate a significant increase in losartan plasma concentrations in patients with liver cirrhosis; losartan should be used with caution in patients with a history of mild or moderate liver dysfunction (<9 points on the Child-Pugh scale). There is no experience with the use of losartan in patients with severe liver dysfunction, so the use of losartan is contraindicated in this group of patients.

Renal dysfunction

Impaired renal function due to suppression of the RAAS has been reported, including renal failure (particularly in patients whose renal function depends on the RAAS, for example, in severe heart failure or pre-existing renal impairment). As with the use of other drugs affecting the RAAS, cases of increased serum urea and creatinine concentrations have been described in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney. These changes in renal function may be reversible and decrease after discontinuation of treatment. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney.

Kidney transplantation

There is no experience with the use of losartan in patients who have recently undergone kidney transplantation, so caution should be exercised when using the drug in such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to treatment with antihypertensive drugs that inhibit the RAAS. For this reason, the use of losartan is not recommended.

Coronary artery disease and cerebrovascular disease

As with the use of any other antihypertensive drugs, an excessive decrease in blood pressure in patients with coronary artery disease or cerebrovascular disease may lead to the development of myocardial infarction or ischemic stroke.

Heart failure

As with the use of other drugs affecting the RAAS, in patients with heart failure with or without renal impairment, there is a risk of developing severe arterial hypotension and acute renal failure.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with the use of other vasodilators, special caution should be exercised when treating patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Differences associated with ethnicity

Similar to other ACE inhibitors, losartan and other ARBs are significantly less effective in lowering blood pressure in black patients compared to patients of other races. This may be due to the higher frequency of low renin levels in the black population with arterial hypertension.

Dual blockade of the RAAS

There is evidence that the simultaneous use of ACE inhibitors, ARBs, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), therefore dual blockade of the RAAS with the combination of losartan with ACE inhibitors or aliskiren is not recommended. If dual blockade of the RAAS is necessary, treatment should be carried out under the supervision of a specialist with frequent and careful monitoring of renal function, water-electrolyte balance, and blood pressure.

The simultaneous use of ARBs, including losartan, with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or patients with moderate and severe renal failure (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients (see section “Contraindications”).

The simultaneous use of ARBs, including losartan, with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

Excipient

The drug contains the dye Ponceau 4R [Ponso 4R], which can cause allergic reactions.

Effect on the ability to drive vehicles and machinery

Studies on the effect of the Hydrochlorothiazide + losartan combination on the ability to drive vehicles or operate machinery have not been conducted. However, it should be taken into account that during treatment with antihypertensive drugs, dizziness or drowsiness may occur when driving or operating machinery, especially at the beginning of treatment or when increasing the dose of the drug.

Overdose

There are no data on specific treatment for overdose of the Hydrochlorothiazide + losartan combination. The drug should be discontinued and the patient should be observed. In case of overdose, symptomatic therapy is indicated: gastric lavage if the drug has been taken recently, as well as elimination of dehydration, electrolyte disturbances, and decreased blood pressure by standard methods (restoration of circulating blood volume and water-electrolyte balance).

Hydrochlorothiazide

The most common manifestations of hydrochlorothiazide overdose are increased diuresis, accompanied by acute fluid loss (dehydration) and electrolyte disturbances (hypokalemia, hyponatremia, hypochloremia). Hydrochlorothiazide overdose may manifest with the following symptoms

• From the cardiovascular system: tachycardia, decreased blood pressure, shock;
• From the nervous system: weakness, confusion, dizziness and calf muscle cramps, paresthesia, impaired consciousness, fatigue;
• From the gastrointestinal tract: nausea, vomiting, thirst;
• From the kidneys and urinary tract: polyuria, oliguria or anuria (due to hemoconcentration);
• Laboratory parameters: hypokalemia, hyponatremia, hypochloremia, alkalosis, increased blood urea nitrogen (especially in patients with renal failure).

Treatment for overdose involves symptomatic and supportive therapy. If the drug was taken recently, induction of vomiting or gastric lavage is indicated to remove hydrochlorothiazide. The absorption of hydrochlorothiazide can be reduced by oral administration of activated charcoal. In case of decreased blood pressure or shock, the circulating blood volume should be replenished by administration of plasma-substituting fluids and the electrolyte deficit (potassium, sodium) should be corrected. In case of respiratory disorders, oxygen inhalation or mechanical ventilation is indicated. Water-electrolyte balance (especially serum potassium levels) and renal function should be monitored until they normalize.

There is no specific antidote. Hydrochlorothiazide is removed by hemodialysis, but the extent of its removal is not established.

Losartan

The most common symptoms of overdose are a pronounced decrease in blood pressure and tachycardia; bradycardia may be a consequence of parasympathetic (vagal) stimulation.

Treatment in case of symptomatic arterial hypotension, supportive infusion therapy is indicated. Losartan and its active metabolite are not removed by hemodialysis.

Drug Interactions

Hydrochlorothiazide

Not recommended drug combinations

Lithium preparations

With simultaneous use of hydrochlorothiazide and lithium preparations, the renal clearance of lithium decreases, which can lead to an increase in lithium plasma concentration and an increase in its toxicity. If simultaneous use of hydrochlorothiazide is necessary, the dose of lithium preparations should be carefully selected, lithium plasma concentration should be regularly monitored, and the drug dose should be adjusted accordingly.

Drug combinations requiring special attention

Drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type

Hydrochlorothiazide should be used with particular caution simultaneously with such drugs as

• Class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, procainamide) and class IC antiarrhythmic drugs (flecainide);
• Class III antiarrhythmic drugs (dofetilide, ibutilide, bretylium tosilate), sotalol, dronedarone, amiodarone;
• Other (non-antiarrhythmic) drugs such as:
  • Neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride), butyrophenones (droperidol, haloperidol); pimozide, sertindole;
  • Antidepressants: tricyclic antidepressants;
  • Selective serotonin reuptake inhibitors (citalopram, escitalopram);
  • Antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin);
  • Macrolides (erythromycin when administered intravenously, azithromycin, clarithromycin. roxithromycin, spiramycin), co-trimoxazole;
  • Antifungal agents: azoles (voriconazole, itraconazole, ketoconazole, fluconazole);
  • Antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
  • Antiprotozoal agents (pentamidine when administered parenterally);
  • Antianginal agents (ranolazine, bepridil);
  • Anticancer agents (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus);
  • Antiemetic agents (domperidone, ondansetron);
  • Agents affecting gastrointestinal motility (cisapride);
  • Antihistamines (astemizole; terfenadine; mizolastine);
  • Other drugs (anagrelide, vasopressin, diphemanil methylsulfate, ketanserin. probucol, propofol, sevoflurane, terlipressin, terodiline, cilostazol).

Due to an increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the “torsades de pointes” type (risk factor – hypokalemia)

Plasma potassium levels should be determined and, if necessary, corrected before starting combination therapy with hydrochlorothiazide and the above-mentioned drugs. Clinical monitoring of the patient, plasma electrolyte levels, and ECG parameters are necessary. In patients with hypokalemia, drugs that do not cause polymorphic ventricular tachycardia of the “torsades de pointes” type should be used.

Drugs that can increase the QT interval

The simultaneous use of hydrochlorothiazide with drugs that can increase the QT interval should be based on a careful assessment for each patient of the ratio of expected benefit and potential risk (possible increase in the risk of developing polymorphic ventricular tachycardia of the “torsades de pointes” type). When using such combinations, it is necessary to regularly record an ECG (to detect QT interval prolongation) and monitor blood potassium levels.

Drugs that can cause hypokalemia: amphotericin B (when administered intravenously), glucocorticoids and mineralocorticoids (when used systemically), tetracosactide (ACTH), glycyrrhizic acid (carbenoxolone, preparations containing licorice root), laxatives that stimulate intestinal motility

Increased risk of hypokalemia with simultaneous use with hydrochlorothiazide (additive effect). Regular monitoring of plasma potassium levels is necessary, and correction if necessary. During therapy with hydrochlorothiazide, it is recommended to use laxatives that do not stimulate intestinal motility.

Cardiac glycosides

Hypokalemia and hypomagnesemia caused by the action of thiazide diuretics enhance the toxicity of cardiac glycosides. With simultaneous use of hydrochlorothiazide and cardiac glycosides, plasma potassium concentration, ECG parameters should be regularly monitored, and therapy should be adjusted if necessary.

Drug combinations requiring attention

Other antihypertensive drugs

Potentiation of the antihypertensive effect of hydrochlorothiazide (additive effect). It may be necessary to adjust the dose of simultaneously prescribed antihypertensive drugs.

It is recommended to stop taking hydrochlorothiazide 2-3 days before starting therapy with ACE inhibitors to prevent the development of symptomatic arterial hypotension. If this is not possible, then the initial dose of ACE inhibitors should be reduced.

Ethanol, barbiturates, antipsychotic agents (neuroleptics), antidepressants, anxiolytics, narcotic analgesics, and general anesthetics

Possible enhancement of the antihypertensive effect of hydrochlorothiazide and potentiation of orthostatic hypotension (additive effect).

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

Possible enhancement of the effect of non-depolarizing muscle relaxants.

Adrenomimetics (pressor amines)

Hydrochlorothiazide may reduce the effect of adrenomimetics such as epinephrine (adrenaline) and norepinephrine (noradrenaline).

NSAIDs, including selective COX-2 inhibitors and high doses of acetylsalicylic acid (>3 g/day)

NSAIDs may reduce the diuretic and antihypertensive effects of hydrochlorothiazide. With simultaneous use, there is a risk of developing acute renal failure due to a decrease in glomerular filtration rate. Hydrochlorothiazide may enhance the toxic effect of high doses of salicylates on the central nervous system.

Oral hypoglycemic agents and insulin

Thiazide diuretics affect glucose tolerance (possible development of hyperglycemia) and reduce the effectiveness of hypoglycemic agents (dose adjustment of hypoglycemic agents may be required).

Hydrochlorothiazide and metformin should be used together with caution due to the risk of lactic acidosis against the background of renal dysfunction caused by hydrochlorothiazide.

Beta-blockers, diazoxide

Simultaneous use of thiazide diuretics (including Hydrochlorothiazide) with beta-blockers or diazoxide may increase the risk of hyperglycemia.

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

Dose adjustment of uricosuric drugs may be required, as Hydrochlorothiazide increases serum uric acid concentration. Thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Amantadine

Thiazide diuretics (including Hydrochlorothiazide) may reduce the clearance of amantadine, lead to an increase in amantadine plasma concentration, and increase the risk of its adverse effects.

Anticholinergic drugs (cholinoceptor antagonists)

Anticholinergic drugs (e.g., atropine, biperiden) increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Cytotoxic (anticancer) drugs

Thiazide diuretics reduce the myelosuppressive effect of cytotoxic drugs (cyclophosphamide and methotrexate).

Methyldopa

Cases of hemolytic anemia have been described with simultaneous use of hydrochlorothiazide and methyldopa.

Antiepileptic drugs (carbamazepine, oxcarbazepine, topiramate)

Risk of symptomatic hyponatremia. With simultaneous use of hydrochlorothiazide and carbamazepine, patient monitoring and control of serum sodium levels are necessary. With simultaneous use of hydrochlorothiazide and topiramate, serum topiramate levels should also be monitored, and if necessary, potassium preparations should be prescribed or the dose of topiramate should be adjusted.

Selective Serotonin Reuptake Inhibitors

Concomitant use with thiazide diuretics may potentiate hyponatremia. Monitoring of plasma sodium levels is necessary.

Cyclosporine

Concomitant use of thiazide diuretics and cyclosporine increases the risk of hyperuricemia and gout exacerbation.

Oral Anticoagulants

Thiazide diuretics may reduce the effect of oral anticoagulants.

Iodinated Contrast Media

Dehydration while taking thiazide diuretics increases the risk of acute renal failure, especially when using high doses of iodinated contrast media. Fluid loss must be compensated before using iodinated contrast media.

Calcium Preparations

Concomitant use may lead to increased blood calcium levels and the development of hypercalcemia due to reduced renal excretion of calcium ions. If concomitant administration of calcium-containing medicines is necessary, plasma calcium levels should be monitored and the dose of calcium preparations should be adjusted.

Anion Exchange Resins (cholestyramine and colestipol)

Anion exchange resins reduce the absorption of hydrochlorothiazide. Single doses of cholestyramine and colestipol reduce the gastrointestinal absorption of hydrochlorothiazide by 85% and 43%, respectively.

Losartan

Cases of decreased concentration of the active metabolite have been described with concomitant use of rifampicin and fluconazole. The clinical significance of this interaction has not been evaluated.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium preparations, or potassium-containing salt substitutes may lead to an increase in plasma potassium levels. Concomitant use of these drugs is not recommended.

Reversible increases in serum lithium concentrations have been reported with concomitant use of lithium preparations with ACE inhibitors, and in very rare cases with ARBs. Caution should be exercised when using lithium preparations concomitantly. If combination use is necessary, careful monitoring of plasma lithium concentrations is recommended.

Concomitant use of angiotensin II receptor antagonists and NSAIDs, for example, selective COX-2 inhibitors, acetylsalicylic acid at doses used for anti-inflammatory effect, and non-selective NSAIDs, may reduce the antihypertensive effect of losartan. Concomitant use of angiotensin II receptor antagonists or diuretics and NSAIDs may lead to an increased risk of worsening renal function, including acute renal failure, and increased plasma potassium levels, especially in patients with pre-existing renal impairment. This combination should be used with caution, especially in elderly patients. Adequate hydration of patients should be ensured and renal function should be monitored after starting combination therapy and periodically during treatment.

In some patients with impaired renal function treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of angiotensin II receptor antagonists may worsen renal impairment. These effects are usually reversible.

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) compared to the use of drugs affecting the RAAS as monotherapy.

Concomitant use of ARBs, including losartan, with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or in patients with moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of losartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Other drugs that cause a decrease in BP, such as tricyclic antidepressants, antipsychotics, baclofen, amifostine concomitant use of losartan with these drugs may increase the risk of arterial hypotension.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.