Losar N

Losartan + hydrochlorothiazide

Film-coated tablets

Round, biconvex, yellow film-coated tablets

Each tablet contains:
Active substances: losartan potassium 50 mg or 100 mg and hydrochlorothiazide 12.5 mg or 25 mg;
Excipients: microcrystalline cellulose, pregelatinized corn starch, lactose monohydrate, magnesium stearate;
Shell composition: hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide (E171), iron oxide yellow (E172).

Agents affecting the renin-angiotensin system. Angiotensin II antagonists and diuretics.

C09DA01

The active ingredients of Losar N are losartan and hydrochlorothiazide.

Losartan and hydrochlorothiazide
It has been proven that the combined use of losartan and hydrochlorothiazide has an additive effect on lowering blood pressure (BP), reducing it to a greater extent than either of the components separately. This is due to the complementary action of both components. In addition, as a result of the diuretic action, hydrochlorothiazide increases the activity of plasma renin and the release of aldosterone, and also reduces the content of potassium and increases the level of angiotensin II in plasma. Losartan blocks all physiologically significant actions of angiotensin II and, through the inhibition of aldosterone, reduces the loss of potassium ions caused by diuretics.

Losartan has been shown to have a mild and transient uricosuric effect. Hydrochlorothiazide slightly increases the concentration of uric acid in the blood plasma; the combination of losartan and hydrochlorothiazide helps to reduce diuretic-induced hyperuricemia.

The antihypertensive effect of losartan and hydrochlorothiazide lasts for 24 hours and persists with continuous treatment. Despite a significant decrease in blood pressure, they do not have a clinically significant effect on heart rate. In clinical studies, after 12 weeks of using losartan + hydrochlorothiazide at a dose of 50/12.5 mg, a decrease in diastolic blood pressure in the sitting position by an average of 13.2 mm Hg was recorded.

Losartan and hydrochlorothiazide effectively reduce blood pressure in men and women, in blacks and other races, in young and elderly (> 65 years old) patients; the drug is effective for any degree of arterial hypertension.

Losartan
Losartan is a synthetic angiotensin II receptor (type AT₁) antagonist that is administered orally. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to AT₁ receptors found in many tissues (e.g. vascular smooth muscle, adrenal glands, kidneys, and heart) and has several important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.

Losartan selectively blocks the AT₁ receptor. Under in vitro and in vivo conditions, losartan and its pharmacologically active carboxylic acid metabolite (E 3174) block all physiologically significant effects of angiotensin II, regardless of the source or route of synthesis.

Losartan does not bind or block other hormone receptors and ion channels that are important for the regulation of the cardiovascular system. In addition, losartan does not inhibit ACE (kininase II), which is responsible for the breakdown of bradykinin. Therefore, there is no increase in the frequency of adverse effects due to bradykinin.
When using losartan, the negative effect of angiotensin II on the formation of renin is inhibited. It leads to an increase in the activity of renin in the blood plasma. An increase in renin activity leads to an increase in the level of angiotensin II in the blood plasma. Despite these increases, antihypertensive activity and a decrease in plasma aldosterone levels persist, indicating effective blocking of the angiotensin II receptor. After discontinuation of losartan therapy, plasma renin activity and angiotensin II concentration returned to baseline within 3 days.

Losartan and its main active metabolite have a higher affinity for the AT₁ receptor than to the AT₂ receptor. The active metabolite is 10-40 times more active than losartan (on a weight basis).

A significant decrease in proteinuria, and periodic release of proteins and immunoglobulin G were reported in patients taking losartan with arterial hypertension, proteinuria without diabetes mellitus. Losartan stabilizes the glomerular filtration rate and reduces the filtration fraction. In general, losartan causes a decrease in serum uric acid levels (average <24 µmol/L), which persists during long-term therapy.

Losartan does not affect autonomic reflexes and does not have a long-term effect on blood plasma norepinephrine levels.
In patients with left ventricular failure, losartan at doses of 25 mg and 50 mg had positive hemodynamic and neurohormonal effects, including an increase in cardiac index and a decrease in wedge pressure in the pulmonary capillaries, a decrease in systemic vascular resistance, mean systemic arterial pressure and heart rate, and a decrease in aldosterone and norepinephrine in circulating blood, respectively. The incidence of arterial hypotension in patients with heart failure was dose-dependent.

Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazides is not precisely known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing the excretion of sodium and chlorine in approximately equal amounts. The diuretic effect of hydrochlorothiazide leads to a decrease in plasma volume, an increase in plasma renin activity and an increase in aldosterone secretion, followed by an increase in the excretion of potassium and bicarbonate in the urine and a decrease in the level of potassium in the blood serum. The relationship between renin and aldosterone is mediated by angiotensin II and therefore the simultaneous use of angiotensin II antagonists reduces the loss of potassium associated with the use of a thiazide diuretic.

After oral administration, the diuretic effect occurs within 2 hours, peaking in about 4 hours, and lasting about 6-12 hours; the antihypertensive effect persists for 24 hours.

Treatment of hypertension in patients who fail to achieve adequate blood pressure control with monotherapy with losartan or hydrochlorothiazide.

Losar N tablets should be taken orally with a glass of chilled boiled water, regardless of the meal. Losar N can be taken with other antihypertensive agents.

Arterial hypertension
Losartan and hydrochlorothiazide are not used as initial therapy, but are used only in patients whose blood pressure is not adequately controlled when using losartan or hydrochlorothiazide alone.

It is recommended to select the dose of each of the components (losartan and hydrochlorothiazide). When clinically necessary, if adequate blood pressure control cannot be achieved, it is possible to switch directly from monotherapy to a fixed combination.

The usual maintenance dose of Losar N is 1 tablet (50 mg of losartan, 12.5 mg of hydrochlorothiazide) once a day. For patients who do not have a sufficient response, the dose may be increased to 2 tablets (50/12.5 mg) or 1 tablet (100/25 mg) once a day. The maximum dose is 2 tablets (50/12.5 mg) or 1 tablet (100/25 mg) once a day. As a rule, the antihypertensive effect is achieved within 3-4 weeks after the start of treatment.

This medicinal product does not provide a 100 mg/12.5 mg dosage, and for patients for whom it is indicated, this combination (at a dose of 100 mg/12.5 mg) from other manufacturers should be used.

Special patient groups

Patients with impaired renal function and patients on hemodialysis
For patients with impaired renal function of moderate severity (creatinine clearance 30-50 ml/min), there is no need to adjust the initial dose of Losar N. It is not recommended to prescribe losartan and hydrochlorothiazide tablets to patients undergoing hemodialysis. The losartan/hydrochlorothiazide combination should not be given to patients with severely impaired renal function (creatinine clearance <30 ml/min).

Patients with impaired liver function
Losartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment.

Elderly patients
In elderly patients, dose adjustment is usually not required.

Patients with circulating fluid deficiency
Correction of fluid and/or sodium deficits is required prior to administration of the losartan/hydrochlorothiazide combination.

Children
There is no experience with the use of Losar N in children and adolescents. Therefore, the use of the combination of losartan and hydrochlorothiazide in children and adolescents under 18 years of age is not recommended

Missed or delayed dose of Losar N
If you forget to take Losar N, you should not make up for the missed dose by taking a double dose. Take the usual dose of the medicine.

Adverse reactions are presented by classes of organ systems and frequency of occurrence: very common (≥ 1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); not known (it is impossible to determine the frequency using the available data).
In clinical studies of losartan potassium and hydrochlorothiazide, no adverse reactions specific to this combination were observed. Adverse reactions were limited to those already reported with losartan potassium and/or hydrochlorothiazide alone.
In controlled clinical trials for primary hypertension, dizziness was the only adverse reaction associated with the use of the drug and was observed in 1% or more of patients.

In the course of post-marketing experience with the use of Losar N, the following adverse reactions have been reported:
Hepatobiliary disorders: hepatitis (rare).
Laboratory tests and instrumental studies interaction: hyperkalemia, increased levels of alanine aminotransferase (rare).

The following adverse reactions have been observed with each of the components and may occur with the combination of losartan potassium/hydrochlorothiazide:

Losartan
The following adverse reactions of losartan were reported during clinical trials, as well as during post-marketing use:

Blood and lymphatic system disorders: anemia, Schonlein-Genoch purpura, ecchymosis, hemolysis (uncommon); thrombocytopenia (not known).

Cardiac disorders: sternalgia, angina pectoris, atrioventricular block II degree, cerebrovascular disorders, myocardial infarction, palpitations, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation) (uncommon).

Vascular disorders: hypotension, orthostatic hypotension, vasculitis (uncommon).

Ear and labyrinth disorders: dizziness, tinnitus (uncommon).

Eye disorders: blurred vision, burning sensation in the eyes, conjunctivitis, decreased visual acuity (uncommon).

Gastrointestinal disorders: abdominal pain, nausea, diarrhea, dyspepsia (common); constipation, toothache, dry mouth, flatulence, gastritis, vomiting, severe constipation (uncommon); pancreatitis (not known).

General disorders and administration site conditions: asthenia, fatigue, chest pain (common); swelling of the face, swelling, fever (uncommon); flu-like symptoms, malaise (not known).

Hepatobiliary disorders: functional disorders of the liver (not known).

Immune system disorders: hypersensitivity: anaphylactic reactions, angioedema, including swelling of the larynx and glottis, with possible further airway obstruction, and / or swelling of the face, lips, pharynx and / or tongue; some patients have a history of angioedema associated with taking other drugs, including ACE inhibitors (rare).

Metabolic and nutritional disorders: anorexia, and gout (uncommon).

Musculoskeletal and connective tissue disorders: muscle cramps, back pain, pain in the legs, myalgia (common); pain in the hands, swelling of the joints, knee pain, musculoskeletal pain, shoulder pain, joint stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness (uncommon); rhabdomyolysis (not known).

Nervous system disorders: headache, dizziness (common); nervousness, paresthesia, peripheral neuropathy, tremor, migraine, fainting (uncommon); taste disturbance (not known).

Mental disorders: insomnia (common); uneasiness, anxiety disorders, panic disorders, confusion, depression, unusual dreams, sleep disturbances, drowsiness, memory impairment (uncommon).

Renal and urinary disorders: impaired renal function, renal failure (common); nocturnal polyuria, frequent urination, urinary tract infection (uncommon).

Reproductive system and breast disorders: decreased libido, erectile dysfunction / impotence (uncommon).

Respiratory, thoracic and mediastinal disorders: cough, upper respiratory tract infections, nasal congestion, sinusitis, dysfunction of the paranasal sinuses (common); discomfort in the throat, pharyngitis, laryngitis, shortness of breath, bronchitis, epistaxis, rhinitis, congestion in the respiratory tract (uncommon).

Skin and subcutaneous tissue disorders: alopecia, dermatitis, dry skin, erythema, redness, photosensitivity, itching, rash, urticaria, increased sweating (uncommon).

Laboratory tests and instrumental studies interaction: hyperkalemia, a slight decrease in hematocrit and hemoglobin, hypoglycemia (common); insignificant increase in the concentration of urea and creatinine (uncommon); increased activity of liver enzymes and bilirubin levels (very rare); hyponatremia (not known).

Hydrochlorothiazide
Blood and lymphatic system disorders: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia (uncommon).

Immune system disorders: anaphylactic reactions (rare).

Metabolic and nutritional disorders: anorexia, hyperglycemia, hyperuricemia, hypokalemia, hyponatremia (uncommon).

Mental disorders: insomnia (uncommon).

Nervous system disorders: headache (common).

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

Eye disorders: blurred (transient) vision, xanthopsia (uncommon).

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

Gastrointestinal disorders: inflammation of the salivary glands, spasms, stomach irritation, nausea, vomiting, diarrhea, constipation (uncommon).

Hepatobiliary disorders: jaundice (intrahepatic cholestasis), pancreatitis (uncommon).

Skin and subcutaneous tissue disorders: photosensitivity, urticaria, toxic epidermal necrolysis (Lyell’s syndrome) (uncommon); skin reactions resembling systemic lupus erythematosus (not known).

Musculoskeletal and connective tissue disorders: muscle spasms (uncommon).

Renal and urinary disorders: glucosuria, interstitial nephritis, renal dysfunction, renal failure (uncommon).

General disorders and administration site conditions: fever, dizziness (uncommon).

In case of adverse reactions, including those not listed in this leaflet, you should consult your healthcare provider.

• hypersensitivity to losartan, sulfonamide derivatives (such as hydrochlorothiazide), or to any other component of Losar N;
• treatment-resistant hypokalemia and hypercalcemia;
• severe liver dysfunction, cholestasis and obstructive diseases of the biliary tract;
• refractory hyponatremia;
• symptomatic hyperuricemia / gout;
• pregnancy or breastfeeding;
• severe renal dysfunction (creatinine clearance <30 ml/min);
• anuria;
• simultaneous use of Losar N with aliskiren in patients with diabetes mellitus or renal insufficiency (glomerular filtration rate <60 ml/min/1.73 m²).

When taking a larger dose than prescribed by a healthcare provider, immediately seek medical advice for timely medical assistance!
There are no specific data on overdose of the combination of losartan and hydrochlorothiazide. Treatment is symptomatic and supportive. In case of an overdose, therapy with Losar N should be discontinued, and the patient should be transferred under strict supervision. If Losar N has been taken recently, it is recommended to induce vomiting, as well as, using known methods, to take preventive measures aimed at eliminating dehydration, electrolyte imbalance, hepatic coma and hypotension.

Losartan
Overdose data are limited. Possible, most likely signs: hypotension, tachycardia, bradycardia (due to parasympathetic (vagus) stimulation). If symptomatic hypotension occurs, supportive treatment should be prescribed.
Neither losartan nor its active metabolite can be removed from the body by hemodialysis.

Hydrochlorothiazide
The most common signs and symptoms are hypokalemia, hypochloremia, hyponatremia (due to low electrolyte levels) and dehydration (due to excessive diuresis). With the simultaneous administration of cardiac glycosides, hypokalemia can lead to an exacerbation of cardiac arrhythmia.
It has not been established to what extent hydrochlorothiazide is excreted during hemodialysis.

Losartan
Rifampicin and fluconazole have been reported to reduce blood levels of the active metabolite. The clinical significance of these interactions has not been evaluated.
As with the use of other drugs that block angiotensin II, the simultaneous use of losartan with potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride) and potassium preparations or salt substitutes containing potassium can lead to an increase in the level of potassium in the blood plasma. The combined use of losartan with these medicines is not recommended.

Like other medicines that affect sodium excretion, losartan may inhibit the excretion of lithium from the body. Thus, with the simultaneous use of lithium salts and angiotensin II antagonists, it is necessary to regularly and carefully monitor the concentration of lithium in the blood plasma.

With the simultaneous use of angiotensin II antagonists with non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of cyclooxygenase-2 (COX-2), acetylsalicylic acid in anti-inflammatory doses) and non-selective NSAIDs, a weakening of the antihypertensive effect may occur. The concomitant use of angiotensin II antagonists or diuretics with NSAIDs may increase the risk of worsening renal function, including possible acute renal failure, and also lead to an increase in serum potassium, especially in patients with existing impaired renal function. This combination of medicines should be used with caution, especially in the elderly. Patients should drink sufficient fluids; in addition, after the start of combination therapy, it is necessary to monitor kidney function and continue to conduct it regularly.
In some patients with impaired renal function taking NSAIDs, including selective COX-2 inhibitors, treatment with angiotensin II antagonists may lead to further deterioration of renal function. This effect is usually reversible.

Dual blockade of the renin-angiotensin-aldosterone system with a combination of an ACE inhibitor, an angiotensin II antagonist, or aliskiren is associated with a higher incidence of side effects such as hypotension, hyperkalemia, and reduced kidney function (including acute renal failure) compared with the use of a single drug means of blocking the renin-angiotensin-aldosterone system.

Combined use with other medicines that cause arterial hypotension, such as tricyclic antidepressants, antipsychotics, baclofen, amifostine, the main or side effect of which is to lower blood pressure, may increase the risk of arterial hypotension.

Hydrochlorothiazide
When used together, the following agents may interact with thiazide diuretics:

Alcohol, barbiturates, and narcotic drugs: The risk of developing orthostatic hypotension may increase.

Antidiabetic medicines (oral hypoglycemic agents and insulin): The use of thiazides may affect glucose tolerance. It may be necessary to change the dose of antidiabetic agents. Caution should be exercised when using metformin, because development of lactic acidosis is possible due to the development of functional renal failure associated with the use of hydrochlorothiazide.

Other antihypertensive agents: Additive effect.

Colestyramine and colestipol: The absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins. Single doses of resins, cholestyramine and colestipol, bind hydrochlorothiazide and, respectively, reduce its absorption in the gastrointestinal tract by 85% or 43%.

Corticosteroids, adrenocorticotropic hormone: Increased electrolyte loss, especially the risk of hypokalemia.

Pressor amines (e.g. epinephrine): May decrease response to pressor amines without precluding use of these agents.

Non-depolarizing musculoskeletal relaxants (e.g. tubocurarine): May increase response to muscle relaxants.

Lithium preparations: Diuretics reduce the renal clearance of lithium and increase the risk of lithium intoxication, so concomitant use is not recommended.

Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol): Dose adjustment of medicines that promote uric acid excretion may be necessary because hydrochlorothiazide can increase serum uric acid concentration. An increase in the dose of probenecid or sulfinpyrazone may be required. The simultaneous use of thiazides may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergics (e.g. atropine, biperiden): An increase in the bioavailability of thiazide diuretics is associated with a decrease in the motor activity of the gastrointestinal tract and the rate of gastric emptying.

Cytotoxic agents (cyclophosphamide, and methotrexate): Thiazides may reduce the renal excretion of cytotoxic agents and increase their myelosuppressive effect.

Salicylates: When high doses of salicylates are used, hydrochlorothiazide may increase their toxic effect on the central nervous system.

Methyldopa: In some cases, hemolytic anemia has been reported with the combined use of hydrochlorothiazide and methyldopa.

Cyclosporine: Co-administration with cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Cardiac glycosides: Hypokalemia or hypomagnesemia induced by thiazides may contribute to the formation of digitalis-induced arrhythmias.

Medicinal products affected by changes in serum potassium: Periodic monitoring of serum potassium and ECG is recommended when Losar N is co-administered with medicinal products that are affected by any change in the content of potassium in the blood serum (e.g. digitalis and antiarrhythmic agents), as well as with the following agents (including antiarrhythmics), which cause pirouette-type tachycardia, while hypokalemia is a predisposing factor for pirouette-type tachycardia (ventricular tachycardia):

• Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, and disopyramide).
• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, and ibutilide).
• Certain antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, and droperidol).
• Other agents (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, and intravenous vincamine).

Calcium salts: Thiazide diuretics can increase the content of calcium in the blood serum due to a decrease in its excretion. If it is necessary to prescribe calcium preparations, the dose is selected under the control of calcium in the blood serum.

Effects on laboratory tests: Due to effects on calcium metabolism, thiazides may interfere with parathyroid function tests.

Carbamazepine: There is a risk of symptomatic hyponatremia. Clinical and biological monitoring is required.

Iodine-containing contrast agents: In case of dehydration caused by the use of thiazide diuretics, there is an increased risk of developing acute renal failure, especially when using high doses of iodine-containing agents. Patients should be rehydrated before administering iodine-containing drugs.

Amphotericin B (parenteral), corticosteroids, adrenocorticotropic hormone and laxatives: Hydrochlorothiazide may exacerbate electrolyte disturbances, in particular hypokalemia.

Your healthcare provider must be informed about all medicines you are taking. Talk to your healthcare provider before you start taking any medicine while you are taking Losar N.

Losartan

Angioedema
Patients with a history of angioedema (swelling of the face, lips, larynx and/or tongue) should be closely monitored.

Arterial hypotension and decrease in circulating blood volume
Patients with decreased circulating blood volume or hyponatremia due to heavy diuretic use, salt restriction, diarrhea or vomiting may develop symptomatic hypotension, especially after the first dose of Losar N. These conditions must be corrected before taking Losar N.

Electrolyte imbalances
Electrolyte disturbances are quite common in patients with impaired renal function and concomitant diabetes, or without it. Therefore, plasma potassium and creatinine clearance should be carefully monitored, especially in patients with heart failure and creatinine clearance of 30 to 50 ml/min.
It is not recommended to take Losar N together with potassium-sparing diuretics, potassium-containing supplements and salt substitutes.

Impaired liver function
According to pharmacokinetic data, in patients with cirrhosis of the liver, a significant increase in the concentration of losartan in blood plasma was detected, therefore, the drug Losar N should be used with caution in patients with a history of mild or moderate hepatic dysfunction. There is no experience with the use of losartan in patients with severe hepatic impairment, therefore, the drug Losar N is contraindicated in this category of patients.

Impaired kidney function
Due to inhibition of the RAAS, renal dysfunction, including renal failure, has been noted (in particular in patients whose kidney function depends on the activity of the RAAS, for example, in patients with severe heart failure or patients with existing renal impairment).

As with the use of other agents that affect the RAAS, with the use of losartan, an increase in the concentration of urea and creatinine in the blood serum was reported in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney; these changes were reversible after discontinuation of therapy. Care must be taken when prescribing losartan to patients with bilateral renal artery stenosis or arterial stenosis of a single kidney.

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

Primary hyperaldosteronism
Patients with primary hyperaldosteronism usually do not respond to therapy with antihypertensive drugs that act through inhibition of the renin-angiotensin system, so the use of Losar N is not recommended.

Coronary heart disease (CHD) and cerebrovascular disease
Like any antihypertensive drug, losartan can cause a significant decrease in blood pressure in patients with CHD and cerebrovascular disease, which can lead to myocardial infarction or stroke.

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

Stenosis of the aortic and mitral valves, obstructive hypertrophic cardiomyopathy
As with other vasodilators, special care is required when prescribing Losar N to patients suffering from aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Ethnic differences
ACE inhibitors, losartan, and other angiotensin antagonists have been observed to reduce blood pressure less effectively in blacks than in non-blacks. Perhaps this is due to the fact that among the representatives of the black race suffering from arterial hypertension, persons with low renin activity predominate.

Pregnancy
ARB II treatment should not be started during pregnancy. Unless it is not possible to replace ARB II with another alternative therapy. The patients planning pregnancy should be switched to antihypertensive therapy with medicines that have a well-established safety profile for pregnant women. If pregnancy occurs, ARB II should be discontinued immediately and other antihypertensive therapy initiated as needed.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, ARB II or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual RAAS blockade with concomitant use of ACE inhibitors, ARB II, or aliskiren is not recommended.

If double blockade is considered absolutely necessary, then it can only be carried out under the supervision of a specialist with careful monitoring of renal function, fluid and electrolyte balance and blood pressure. ACE inhibitors and ARB II should not be used concomitantly in patients with diabetic nephropathy.

Hydrochlorothiazide

Arterial hypotension, water and electrolyte imbalance
As with any antihypertensive agent, symptomatic hypotension may occur in some patients. It is necessary to monitor patients in order to timely detect clinical symptoms of fluid and electrolyte disorders, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia, which can develop with intercurrent diarrhea or vomiting. In these patients, it is necessary to regularly monitor the content of electrolytes in the blood serum. In hot weather, patients suffering from edema may experience dilutional hyponatremia.

Metabolic and endocrine effects
Thiazide therapy may reduce glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required. During treatment with thiazides, latent diabetes mellitus may manifest.

Thiazides can reduce the excretion of calcium in the urine and cause an occasional and slight increase in serum calcium. Severe hypercalcemia may indicate the presence of latent hyperparathyroidism. Before examining the function of the parathyroid glands, thiazides should be discontinued.
An increase in plasma cholesterol and triglyceride levels may also be associated with thiazide diuretic therapy.

In some patients, treatment with thiazides may lead to hyperuricemia and/or the development of gout. Since losartan reduces the concentration of uric acid, its combination with hydrochlorothiazide reduces the severity of diuretic-induced hyperuricemia.

Impaired liver function
Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as they can cause intrahepatic cholestasis, which, with minimal disturbance of water and electrolyte balance, can progress to hepatic coma.
Losar N is contraindicated in patients with severe hepatic impairment.

Other states
In patients taking thiazides, hypersensitivity reactions may occur regardless of a history of allergic conditions or bronchial asthma. Relapses or worsening of systemic lupus erythematosus have been reported in patients treated with thiazides.

Special information on excipients
Losar N contains lactose. Patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency syndrome, or glucose-galactose malabsorption syndrome should not take Losar N.

Consult your healthcare provider before taking Losar N if you have one of the diseases or conditions listed above.

Pregnancy

ARB II
The use of ARB II is not recommended in the first trimester of pregnancy and is contraindicated in the second and third trimesters of pregnancy.
Epidemiological data on the risk of teratogenicity when taking ACE inhibitors in the first trimester of pregnancy do not allow a definitive conclusion, but some increased risk cannot be ruled out. There are no controlled epidemiological data associated with the use of ARB II, but a similar risk may exist for this class of medicines. Unless it is not possible to replace ARB II with another alternative therapy, patients planning pregnancy should be switched to antihypertensive therapy with drugs that have a well-established safety profile for pregnant women. If pregnancy occurs, ARB II (including Losar N) should be stopped immediately and, if necessary, other antihypertensive therapy should be prescribed.

When using ARB II in the second and third trimesters of pregnancy, a manifestation of fetotoxic effects (decrease in kidney function, oligohydramnios, delayed ossification of the skull bones), as well as neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) were established.

If a woman was taking an ARB II during the second trimester of pregnancy, an ultrasound is recommended to determine the condition of the fetal kidneys and skull bones.
Newborns whose mothers took ARB II should be under close medical supervision due to the possible development of arterial hypotension.

Hydrochlorothiazide
Experience with the use of hydrochlorothiazide during pregnancy, especially in the first trimester, is limited. Data from animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the mechanism of the pharmacological action of hydrochlorothiazide, when it is used in the second and third trimesters of pregnancy, there may be a violation of fetoplacental perfusion and the development of jaundice in the fetus or newborn, as well as electrolyte imbalance and thrombocytopenia.

Hydrochlorothiazide should not be used in gestational edema, gestational hypertension, or pregnancy toxicity due to the risk of decreased plasma volume and development of placental hypoperfusion in the absence of a positive effect on the course of the disease.

Breast-feeding
There are no data on the excretion of losartan into breast milk. In this regard, it is not recommended to use Losar N during breast-feeding. Alternative treatment with medicinal products with a known safety profile during breast-feeding is preferred, especially when feeding newborns and premature infants.
Hydrochlorothiazide is excreted into breast milk in small amounts. High doses of thiazides, leading to a significant increase in urine output, may interfere with milk production. The use of Losar N during breast-feeding is not recommended. If necessary, low doses should be prescribed.

Studies of the effect on the ability to drive vehicles and work with mechanisms have not been conducted. However, when driving or operating machinery, the possibility of dizziness or drowsiness during antihypertensive therapy should be considered, especially at the beginning of treatment or when the dose is increased.

15 tablets in a blister pack made of three-layer film (PVC/PE/PVDC) and a flexible aluminum foil pack, or 14 tablets in a blister pack made of OPA/Al/PVC (oriented polyamide / aluminum / polyvinylchloride) blister foil and flexible aluminum foil packaging. Two blister packs with a patient information leaflet in an outer carton.

Protect from light and moisture. Store at a temperature not exceeding 25°C.
Keep out of the reach of children.

2 years. Do not use after the expiry date.

State enterprise ACADEMPHARM
220141, 5/3 Kuprevicha Street, Minsk, Belarus
Phone / Fax +375 17 268 63 64
production@academpharm.by
To report adverse reactions use the electronic application form on the manufacturer’s website: https://academpharm.by/en