Losartan-N Richter (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter-Rus, JSC (Russia)

ATC Code

C09DA01 (Losartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Losartan (Rec.INN registered by WHO)

Dosage Forms

	Losartan-N Richter	Film-coated tablets, 50 mg+12.5 mg: 30 pcs.
		Film-coated tablets, 100 mg+12.5 mg: 30 pcs.
		Film-coated tablets, 100 mg+25 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brownish-yellow, round, biconvex, with an engraving “C23” on one side.

Excipients: magnesium stearate – 3.25 mg, lactose monohydrate – 63 mg, pregelatinized starch – 25 mg, microcrystalline cellulose – 96.25 mg.

Film coating composition Opadry orange code: 85F23426 (polyvinyl alcohol – 4 mg, titanium dioxide – 2.2783 mg, macrogol – 2.02 mg, talc – 1.48 mg, iron oxide yellow dye – 0.166 mg, sunset yellow FCF (E110) – 0.05 mg, iron oxide black dye – 0.0057 mg).

10 pcs. – blisters (3) – cardboard packs.

Film-coated tablets yellow, oval, biconvex, with an engraving “C25” on one side; the other side is without engraving.

Excipients: magnesium stearate – 6.5 mg, lactose monohydrate – 126 mg, pregelatinized starch – 50 mg, microcrystalline cellulose – 205 mg.

Film coating composition Opadry II yellow code: 85F27044 (polyvinyl alcohol – 8 mg, titanium dioxide – 4.578 mg, macrogol – 4.04 mg, talc – 2.96 mg, iron oxide yellow dye – 0.4 mg, sunset yellow FCF (E110) – 0.2 mg, iron oxide black dye – 0.002 mg).

10 pcs. – blisters (3) – cardboard packs.

Film-coated tablets brownish-yellow, oval, biconvex, with an engraving “C24” on one side.

Excipients: magnesium stearate – 6.5 mg, lactose monohydrate – 126 mg, pregelatinized starch – 50 mg, microcrystalline cellulose – 192.5 mg.

Film coating composition Opadry orange code: 85F23426 (polyvinyl alcohol – 8 mg, titanium dioxide – 4.5566 mg, macrogol – 4.04 mg, talc – 2.96 mg, iron oxide yellow dye – 0.332 mg, sunset yellow FCF (E110) – 0.1 mg, iron oxide black dye – 0.0114 mg).

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (angiotensin II receptor antagonist + diuretic)

Pharmacological Action

The components of the drug Losartan-N Richter have an additive antihypertensive effect, reducing blood pressure to a greater extent than each of the components separately. This effect is due to the complementary action of both components.

Due to the diuretic effect, Hydrochlorothiazide increases plasma renin activity, stimulates aldosterone secretion, increases the concentration of angiotensin II, and reduces serum potassium levels. Taking losartan blocks all physiological effects of angiotensin II and, due to the suppression of aldosterone effects, may help reduce potassium loss associated with diuretic intake.

Losartan has a weak and transient uricosuric effect.

Hydrochlorothiazide causes a slight increase in plasma uric acid concentration. The combination of losartan and hydrochlorothiazide helps reduce the severity of diuretic-induced hyperuricemia.

Losartan and Hydrochlorothiazide effectively reduce blood pressure in men and women, in Black and other races, in young (<65 years) and elderly (≥65 years) patients. Losartan-N Richter is effective in any degree of arterial hypertension.

Losartan

Losartan is a selective, orally active angiotensin II AT₁ receptor antagonist. It does not inhibit kininase II, the enzyme that catalyzes the conversion of angiotensin I to angiotensin II.

Angiotensin II is a potent vasoconstrictor, the primary active hormone of the renin-angiotensin-aldosterone system (RAAS), and a crucial pathophysiological link in the development of arterial hypertension.

Angiotensin II binds to AT₁ receptors located in many tissues (vascular smooth muscle, adrenal glands, kidneys, and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation.

Losartan and its pharmacologically active metabolite (E 3174) block all physiological effects of angiotensin II, both in vitro and in vivo, regardless of the source or synthesis pathway.

Losartan selectively binds to AT₁ receptors and does not bind to or block receptors for other hormones and ion channels that play an important role in cardiovascular regulation. Furthermore, Losartan does not inhibit angiotensin-converting enzyme (ACE) and, accordingly, does not prevent the breakdown of bradykinin; therefore, side effects indirectly related to bradykinin (e.g., angioedema) occur quite rarely.

When using losartan, the lack of negative feedback on renin secretion leads to an increase in plasma renin activity. Increased renin activity leads to an increase in plasma angiotensin II. However, antihypertensive activity and a decrease in plasma aldosterone concentration persist, indicating effective blockade of angiotensin II receptors.

Losartan and its active metabolite have a greater affinity for angiotensin I receptors than for angiotensin II receptors. The active metabolite is 10-40 times more potent than losartan.

After a single oral dose, the antihypertensive effect (reduction in systolic and diastolic blood pressure) peaks at 6 hours and then gradually decreases over 24 hours.

The maximum antihypertensive effect develops 3-6 weeks after starting losartan.

In patients with arterial hypertension without concomitant diabetes mellitus with proteinuria (more than 2 g/day), the use of losartan significantly reduces proteinuria, albumin excretion, and immunoglobulin G excretion.

Losartan at a dose of 150 mg/day does not affect serum triglyceride, total cholesterol, and HDL cholesterol concentrations in patients with arterial hypertension. At the same dose, Losartan does not affect fasting blood glucose levels.

Hydrochlorothiazide

The mechanism of the antihypertensive action of thiazides is not fully known. Thiazides usually do not affect normal blood pressure. Hydrochlorothiazide acts on electrolyte reabsorption in the distal renal tubules and approximately equally increases the excretion of sodium and chloride ions. Natriuresis may be accompanied by a slight loss of potassium and bicarbonate ions. When taken orally, the diuretic effect develops within 2 hours, peaks on average at 4 hours, and lasts from 6 to 12 hours.

Pharmacokinetics

Absorption

Losartan. When taken orally, Losartan is well absorbed and undergoes first-pass metabolism in the liver, resulting in the formation of an active carboxylated metabolite and inactive metabolites. Systemic bioavailability is approximately 33%. Mean C_max values for losartan and its active metabolite are reached at 1 hour and 3-4 hours, respectively. When losartan was taken with food, no clinically significant effect on the plasma concentration profile of losartan was identified.

Hydrochlorothiazide. When taken orally, Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. The time to reach C_max is 1.5-3 hours.

Distribution

Losartan. Losartan and its active metabolite are more than 99% bound to plasma proteins (primarily albumin). The V_d of losartan is 34 L. Studies in rats have shown that Losartan practically does not cross the blood-brain barrier.

Hydrochlorothiazide. Hydrochlorothiazide is 40-60% bound to plasma proteins, crosses the placental barrier (but not the blood-brain barrier), and passes into breast milk.

Metabolism

Losartan. Approximately 14% of the losartan dose administered intravenously or orally is converted to its active metabolite. After oral administration or intravenous administration of radiolabeled carbon losartan (¹⁴C losartan), the radioactivity in circulating plasma is primarily due to the presence of losartan and its active metabolite. Low efficiency of conversion of losartan to its active metabolite was observed in approximately 1% of patients participating in the study.

In addition to the active metabolite, biologically inactive metabolites are formed as a result of hydroxylation of the butyl side chain, including two main metabolites and one minor one – N-2-tetrazole-glucuronide.

Excretion

Losartan. The plasma clearance of losartan and its active metabolite is about 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. When losartan is taken orally, about 4% of the dose is excreted by the kidneys unchanged, and about 6% of the dose is excreted as the active metabolite. When losartan is taken orally in doses up to 200 mg, Losartan and its active metabolite have linear pharmacokinetics.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal T_1/2 of approximately 2 hours and 6-9 hours, respectively. With a single daily dose of 100 mg, neither Losartan nor its active metabolite accumulates significantly in plasma. Losartan and its metabolites are excreted by the kidneys and through the intestine with bile. After oral administration of ¹⁴C losartan, about 35% of the radioactivity is found in the urine and 58% in the feces.

Hydrochlorothiazide. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys. T_1/2 ranges from 5.6 to 14.8 hours. At least 61% of the orally administered dose is excreted unchanged within 24 hours.

Pharmacokinetics in specific patient groups

Losartan + Hydrochlorothiazide

Elderly patients. The plasma concentrations of losartan and its active metabolite and the absorption rate of hydrochlorothiazide in elderly patients with hypertension do not differ significantly from these parameters in young patients with hypertension.

Losartan

Patients with impaired liver function. After oral administration in patients with mild to moderate alcoholic liver cirrhosis, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young male volunteers.

Patients with impaired renal function. Plasma concentrations of losartan in patients with creatinine clearance greater than 10 ml/min did not differ from those in patients with normal renal function. When comparing AUC in patients with normal renal function, the AUC of losartan in patients on hemodialysis was approximately 2 times higher. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite cannot be removed by hemodialysis.

Gender. The plasma concentration of losartan was 2 times higher in women with hypertension compared to men with hypertension. This apparent pharmacokinetic difference has no clinical significance. Concentrations of the active metabolite did not differ between men and women.

Indications

• Treatment of arterial hypertension in patients for whom combination therapy is indicated;
• Reduction of the risk of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy.

ICD codes

Dosage Regimen

The drug Losartan-N Richter is intended for the treatment of patients in whom adequate blood pressure control is not achieved with losartan or hydrochlorothiazide as monotherapy.

The drug Losartan-N Richter should be taken orally, regardless of meals, with a sufficient amount of liquid.

The drug Losartan-N Richter can be taken in combination with other antihypertensive agents.

Arterial hypertension

The usual maintenance dose is 1 tablet of Losartan-N Richter (50 mg losartan + 12.5 mg hydrochlorothiazide) once daily. For patients with an insufficient response to therapy, the dose may be increased to 1 tablet of Losartan-N Richter (100 mg losartan + 12.5 mg hydrochlorothiazide) or 1 tablet of Losartan-N Richter (100 mg losartan + 25 mg hydrochlorothiazide) once daily.

The maximum dose is 1 tablet of Losartan-N Richter (100 mg losartan + 25 mg hydrochlorothiazide) once daily. In general, the antihypertensive effect is achieved within 3-4 weeks after starting therapy.

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

1 tablet of Losartan-N Richter (100 mg losartan + 12.5 mg hydrochlorothiazide) once daily. The dose of Losartan-N Richter (100 mg losartan + 12.5 mg hydrochlorothiazide) is prescribed to patients in whom target blood pressure levels are not achieved while taking 1 tablet of Losartan-N Richter (50 mg losartan + 12.5 mg hydrochlorothiazide). If necessary, the dose can be increased to 2 tablets of Losartan-N Richter (50 mg + 12.5 mg) (total 100 mg losartan and 25 mg hydrochlorothiazide) once daily.

Use in patients with impaired renal function or patients on hemodialysis

No initial dose adjustment is required for patients with moderate renal impairment (creatinine clearance 30-50 ml/min). Losartan-N Richter is not recommended for patients on hemodialysis. The use of Losartan-N Richter is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min) (see section “Contraindications”).

Use in patients with reduced blood volume

Before starting therapy with Losartan-N Richter, blood volume and/or plasma sodium levels must be restored.

Use in elderly patients

No initial dose adjustment is required for elderly patients.

Use in patients with impaired liver function

Losartan-N Richter is contraindicated in patients with severe liver impairment.

Adverse Reactions

Undesirable adverse reactions are presented by system-organ classes in accordance with the MedDRA classification and with the frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

In clinical studies of the Losartan/Hydrochlorothiazide combination, no adverse events specific to this combination drug were observed. Adverse events were limited to those previously reported with the use of losartan and hydrochlorothiazide separately.

The following adverse events have been observed during post-marketing use of the Losartan/Hydrochlorothiazide combination.

Hepatobiliary disorders rare – hepatitis.

Investigations rare – hyperkalemia, increased hepatic transaminases.

The following adverse events have been observed with the use of losartan and hydrochlorothiazide separately.

Losartan

Blood and lymphatic system disorders uncommon – anemia, Henoch-Schönlein purpura, ecchymosis, hemolytic anemia; frequency not known – thrombocytopenia.

Cardiac disorders uncommon – marked decrease in blood pressure, orthostatic hypotension, sternalgia (chest pain), angina pectoris, second-degree AV block, cerebrovascular disorders, myocardial infarction, palpitations, arrhythmia (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation), vasculitis; frequency not known – dose-dependent orthostatic effect.

Ear and labyrinth disorders uncommon – vertigo, tinnitus.

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

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

Hepatobiliary disorders frequency not known – impaired liver function.

Immune system disorders rare – hypersensitivity reactions – anaphylactic reactions, angioedema, including laryngeal and glottis edema leading to airway obstruction, and/or swelling of the face, lips, pharynx and/or tongue; in some of these patients, angioedema has been observed in the past in connection with the use of other drugs, including ACE inhibitors.

Metabolism and nutrition disorders uncommon – anorexia, gout.

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

Nervous system disorders common – headache, dizziness; uncommon – hyperexcitability, paresthesia, peripheral neuropathy, tremor, migraine, syncope.

Psychiatric disorders Common – insomnia; Uncommon – anxiety, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorders, somnolence, memory impairment; Frequency unknown – dysgeusia.

Urinary system disorders Common – renal impairment, renal failure; Uncommon – nocturia, frequent urination, urinary tract infections.

Reproductive system and breast disorders Uncommon – decreased libido, erectile dysfunction/impotence.

Respiratory system disorders Common – cough, upper respiratory tract infections, nasal congestion, sinusitis, sinus disorders; Uncommon – throat discomfort, pharyngitis, laryngitis, dyspnea, bronchitis, epistaxis, rhinitis, respiratory tract congestion.

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

General disorders Common – asthenia, fatigue, chest pain; Uncommon – facial edema, pyrexia; Frequency unknown – flu-like symptoms, discomfort.

Investigations Common – hyperkalemia, slight decrease in hematocrit and hemoglobin, hypoglycemia; Uncommon – slight increase in serum urea and creatinine; Very rare – increased liver enzymes and bilirubin concentration; Frequency unknown – hyponatremia.

Hydrochlorothiazide

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

Immune system disorders Rare – anaphylactic reactions.

Metabolism and nutrition disorders Uncommon – anorexia, hyperglycemia, hyperuricemia, hypokalemia, hyponatremia.

Psychiatric disorders Uncommon – insomnia.

Nervous system disorders Common – cephalalgia (headache).

Eye disorders Uncommon – transient blurred vision, xanthopsia.

Cardiac disorders Uncommon – necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory system disorders Uncommon – respiratory distress syndrome, including pneumonia and pulmonary edema.

Gastrointestinal disorders Uncommon – sialadenitis, cramps, gastric irritation, nausea, vomiting, diarrhea, constipation, pancreatitis.

Hepatobiliary disorders: Uncommon – jaundice (intrahepatic cholestasis).

Skin and subcutaneous tissue disorders Uncommon – photosensitivity, urticaria, toxic epidermal necrolysis; Frequency unknown – cutaneous lupus erythematosus manifestations.

Musculoskeletal and connective tissue disorders Uncommon – muscle cramps.

Renal and urinary disorders Uncommon – glycosuria, interstitial nephritis, renal dysfunction, renal failure.

General disorders Uncommon – pyrexia, dizziness.

Contraindications

• Hypersensitivity to the components of the drug and to other sulfonamide derivatives;
• Anuria;
• Severe arterial hypotension;
• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Cholestasis;
• Obstructive biliary tract diseases;
• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Dehydration;
• Uncorrectable hypokalemia or hypercalcemia;
• Refractory hyponatremia;
• Symptomatic hyperuricemia/gout;
• Pregnancy;
• Breastfeeding period;
• Women of reproductive age planning pregnancy;
• Age under 18 years (efficacy and safety not established);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Concomitant use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or renal impairment (GFR less than 60 ml/min/1.73 m²).

The drug contains lactose, therefore it should not be prescribed to patients with rare hereditary lactose intolerance, lactase deficiency or glucose/galactose malabsorption.

With caution

Patients with water-electrolyte imbalance, for example, due to diarrhea or vomiting (hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia); patients with primary hyperaldosteronism; hyperkalemia.

Patients with renal failure (creatinine clearance 30-50 ml/min); hepatic failure (less than 9 points on the Child-Pugh scale); bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; coronary artery disease; heart failure with life-threatening arrhythmias; cerebrovascular diseases; aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy; diabetes mellitus, hypercalcemia; with a burdened allergic history and bronchial asthma; as well as with systemic connective tissue diseases (including systemic lupus erythematosus); hypovolemia (including due to the use of high doses of diuretics); as well as with concomitant use with NSAIDs, including COX-2 inhibitors; acute attack of myopia and secondary angle-closure glaucoma; history of angioedema; condition after kidney transplantation (no experience of use); chronic heart failure of functional class IV according to the NYHA classification; age over 75 years, use in patients of Black race.

Use in Pregnancy and Lactation

Pregnancy

The use of Losartan-H Richter during pregnancy is contraindicated. If pregnancy is detected during the course of therapy with Losartan-H Richter, the drug should be discontinued immediately. Patients taking Losartan-H Richter and planning pregnancy should be switched to alternative drugs that have confirmed safety data for use during pregnancy.

Drugs that act directly on the RAAS can cause serious damage and death to the developing fetus, therefore, when pregnancy is diagnosed, Losartan-H Richter should be discontinued immediately.

Although there is no experience with the use of Losartan-H Richter in pregnant women, preclinical animal studies have shown that taking losartan leads to the development of serious embryonic and neonatal damage and fetal or offspring death. It is believed that the mechanism of these phenomena is due to the effect on the RAAS.

Fetal renal perfusion, which depends on the development of the RAAS, appears in the second trimester of pregnancy, so the risk to the fetus increases if Losartan-H Richter is used in the second or third trimester of pregnancy.

The use of drugs affecting the RAAS in the second or third trimester of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include skull hypoplasia, anuria, arterial hypotension, renal failure and death.

The adverse outcomes listed above are usually due to the use of drugs affecting the RAAS in the second or third trimester of pregnancy. Most epidemiological studies on the development of fetal abnormalities after the use of antihypertensive drugs in the first trimester of pregnancy did not reveal differences between drugs affecting the RAAS and other antihypertensive drugs. When prescribing antihypertensive therapy to pregnant women, it is important to optimize possible outcomes for the mother and fetus.

If it is impossible to select alternative therapy to replace therapy with drugs affecting the RAAS, the patient should be informed about the possible risk of therapy for the fetus. Periodic ultrasound examinations should be performed to assess the intra-amniotic space. If oligohydramnios is detected, Losartan-H Richter should be discontinued unless it is vital for the mother. Depending on the week of pregnancy, appropriate fetal tests should be performed. Patients and physicians should be aware that oligohydramnios may not be detected until irreversible fetal damage has occurred. Newborns whose mothers took Losartan-H Richter during pregnancy should be carefully monitored for arterial hypotension, oliguria and hyperkalemia.

Thiazides cross the placental barrier and are detected in cord blood. Routine use of diuretics in healthy pregnant women is not recommended, as it exposes the mother and fetus to unnecessary risks, namely the development of fetal jaundice and neonatal jaundice, thrombocytopenia and other possible adverse reactions that have been observed in adult patients. Diuretics do not prevent the development of preeclampsia, and there is no reliable evidence that they are effective in the treatment of preeclampsia.

Breastfeeding period

There are no data on whether Losartan passes into breast milk. Thiazides pass into breast milk. Since many drugs are excreted in breast milk and there is a risk of developing possible adverse effects in the breastfed child, a decision should be made to discontinue breastfeeding or to discontinue the drug, taking into account the need for it for the mother.

Use in Hepatic Impairment

Contraindicated in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale), with cholestasis, biliary tract obstruction.

The drug should be prescribed with caution in hepatic insufficiency (less than 9 points on the Child-Pugh scale).

Use in Renal Impairment

Contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min), anuria.

With caution: bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, renal failure (creatinine clearance 30-50 ml/min).

Pediatric Use

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

Geriatric Use

The drug should be prescribed with caution to patients over 75 years of age.

Special Precautions

Losartan-H Richter can be prescribed with other antihypertensive agents.

Losartan

Hypersensitivity/Angioedema

Patients with a history of angioedema of the face, lips, tongue, epiglottis and larynx should be under close medical supervision.

Symptomatic arterial hypotension

Symptomatic hypotension may develop in patients with reduced circulating blood volume and/or hyponatremia caused by diuretic use, salt restriction, diarrhea or vomiting, especially after the first dose of the drug. These conditions should be corrected before starting Losartan-H Richter.

Water-electrolyte imbalance

Water-electrolyte imbalances are quite common in patients with renal failure with or without concomitant diabetes mellitus. Therefore, plasma potassium levels and creatinine clearance should be carefully monitored, especially in patients with chronic heart failure and creatinine clearance of 30-50 ml/min.

It is not recommended to take Losartan-H Richter concomitantly with potassium-sparing diuretics, potassium-containing dietary supplements and salt substitutes.

Hepatic impairment

Pharmacokinetic data indicate that the plasma concentration of losartan is significantly increased in patients with liver cirrhosis, so patients with a history of liver disease should use the drug at a lower dose.

Renal impairment

Due to inhibition of the RAAS, changes in renal function, including renal failure, have been observed in some susceptible patients. These changes were reversible and disappeared after discontinuation of therapy.

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, an increase in serum urea and creatinine was observed, usually reversible after discontinuation of treatment. It was more common in patients with renal failure.

Kidney transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive therapy that acts by inhibiting the RAAS. Thus, the use of Losartan-H Richter is not recommended.

Coronary artery disease and cerebrovascular diseases

A sharp decrease in blood pressure during therapy with Losartan-H Richter, as with other antihypertensive drugs, in patients with ischemic cardiovascular and cerebrovascular diseases may lead to the development of acute myocardial infarction or stroke.

Chronic heart failure

In patients with chronic heart failure, with or without renal impairment, the use of Losartan-H Richter, like other agents affecting the RAAS, increases the risk of a sharp decrease in blood pressure and acute renal failure. In patients whose renal function depends on the state of the RAAS (for example, in CHF of functional class III-IV according to the NYHA classification, with or without renal impairment), therapy with drugs affecting the RAAS may be accompanied by sharp arterial hypotension, oliguria and/or progressive azotemia, in rare cases – acute renal failure. The development of the listed disorders due to suppression of RAAS activity while taking angiotensin II receptor antagonists cannot be excluded.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

Caution should be exercised when using Losartan-H Richter in patients with aortic stenosis, mitral stenosis and hypertrophic obstructive cardiomyopathy.

Interaction with drugs affecting the RAAS

Dual blockade of the RAAS with angiotensin II receptor antagonists, ACE inhibitors or aliskiren-containing drugs is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and renal impairment (including acute renal failure) compared with monotherapy. Blood pressure, renal function and electrolyte levels should be monitored in patients who are simultaneously using several drugs that affect the RAAS. Concomitant use of aliskiren with drugs containing Hydrochlorothiazide and Losartan is not recommended in patients with diabetes mellitus and in patients with renal impairment (GFR <60 ml/min/1.73 m²).

Racial differences

It should be taken into account that angiotensin II receptor antagonists, including Losartan, are less effective for the treatment of arterial hypertension in patients of the Black race than in patients of other races.

Hydrochlorothiazide

Arterial hypotension and water-electrolyte imbalance

As with the use of any antihypertensive drugs, symptomatic arterial hypotension may be observed in some patients. Patients should be monitored for timely detection of clinical symptoms of water-electrolyte imbalance (for example, dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia), which may develop with diarrhea or vomiting. In these patients, regular monitoring of serum electrolyte levels should be performed.

Metabolic and endocrine effects

Thiazide diuretic therapy may impair glucose tolerance; in some cases, dose adjustment of hypoglycemic agents, including insulin, may be required.

Thiazide diuretics may reduce renal calcium excretion and cause hypercalcemia. Severe hypercalcemia may be a symptom of latent hyperparathyroidism. Due to its effect on calcium metabolism, Hydrochlorothiazide may distort the results of parathyroid function tests. The thiazide diuretic should be discontinued before testing parathyroid function.

Hydrochlorothiazide may increase cholesterol and triglyceride levels, provoke the occurrence of hyperuricemia and/or gout (since Losartan reduces uric acid levels, the severity of diuretic-induced hyperuricemia is reduced). During treatment with the drug, regular monitoring of plasma potassium, glucose, urea and lipid levels is necessary.

Hydrochlorothiazide may give positive results during doping control.

There are reports of exacerbation or progression of systemic lupus erythematosus while taking thiazide diuretics.

Hepatic impairment

Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as this may lead to the development of intrahepatic cholestasis, which, in combination with water-electrolyte imbalance, may lead to the development of hepatic coma.

Acute attack of myopia and angle-closure glaucoma

Cases of transient myopia and acute development of angle-closure glaucoma have been reported with the use of hydrochlorothiazide. Risk factors for the acute development of angle-closure glaucoma may include a history of allergic reactions to sulfonamide derivatives and penicillin. Symptoms: sudden onset, sharp decrease in vision or eye pain, usually occurring within a few hours to a week after starting therapy. An untreated attack of angle-closure glaucoma can lead to permanent vision loss. First of all, hydrochlorothiazide should be discontinued. If intraocular pressure does not decrease after discontinuation of hydrochlorothiazide, medication or surgical treatment may be required.

It is not recommended to consume alcoholic beverages during treatment, as alcohol enhances the antihypertensive effect of the drug.

Excipients

The drug contains lactose, therefore patients with rare hereditary lactose intolerance, lactase deficiency or glucose/galactose malabsorption should not take this drug.

The drug Losartan-H Richter contains the dye sunset yellow, which may cause allergic reactions.

Effect on the ability to drive vehicles and mechanisms

Studies on the effect on the ability to drive vehicles and mechanisms have not been conducted. Nevertheless, when driving vehicles or mechanisms, it should be taken into account that dizziness or drowsiness may occur when taking antihypertensive drugs, especially at the initial stage of treatment or when increasing the dose.

Overdose

Symptoms

Losartan – pronounced decrease in blood pressure, tachycardia, pronounced bradycardia (as a result of vagal stimulation).

Hydrochlorothiazide – loss of electrolytes (hypokalemia, hypochloremia, hyponatremia), as well as dehydration resulting from excessive diuresis.

Treatment

Symptomatic and supportive therapy. If the drug was taken recently, gastric lavage should be performed; if necessary, correct water-electrolyte imbalances.

Losartan and its active metabolites are not removed by hemodialysis.

It has not been established to what extent Hydrochlorothiazide can be removed from the body by hemodialysis.

Drug Interactions

Losartan

Clinical pharmacokinetic studies have not revealed clinically significant interactions with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin. Rifampicin reduces the concentration of the active metabolite. The clinical significance of this interaction has not been established.

The combination of losartan, like other agents that block angiotensin II or its effects, with potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride, eplerenone), potassium-containing dietary supplements, or potassium salts may lead to an increase in serum potassium levels. Concomitant use of these drugs is not recommended.

Losartan affects sodium excretion and may reduce lithium excretion. Therefore, serum lithium concentrations should be monitored when lithium is coadministered with angiotensin II receptor antagonists.

NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid at doses ≥3 g/day, may reduce the effect of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be attenuated by NSAIDs, including COX-2 inhibitors.

Concomitant use of angiotensin II receptor antagonists or diuretics and NSAIDs may increase the risk of impaired renal function, including the risk of acute renal failure, and may also lead to an increase in serum potassium levels, especially in patients with pre-existing renal impairment. These effects are usually reversible, so the simultaneous use of these drugs should be conducted with caution in patients with impaired renal function and in elderly patients. Patients should consume adequate amounts of fluid. After initiation of combination therapy, renal function should be monitored and subsequently monitored regularly.

Concomitant administration with tricyclic antidepressants, antipsychotic agents, baclofen, amifostine may increase the risk of arterial hypotension.

Dual blockade of the RAAS using angiotensin II receptor antagonists, ACE inhibitors, or aliskiren (a renin inhibitor) is associated with an increased risk of hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) compared to monotherapy. Regular monitoring of blood pressure, renal function, and blood electrolyte levels is necessary in patients taking Losartan-H Richter and other drugs affecting the RAAS simultaneously. Losartan-H Richter should not be used concomitantly with aliskiren in patients with diabetes mellitus. Concomitant use of Losartan-H Richter and aliskiren should be avoided in patients with renal impairment (GFR less than 60 ml/min/1.73 m²). The highest risk is in patients with an established diagnosis of atherosclerosis, heart failure, and diabetes mellitus (with complications). The issue of using dual RAAS blockade (e.g., by simultaneous use of an ACE inhibitor and an angiotensin II receptor antagonist) should be decided on a case-by-case basis with careful monitoring of renal function. ACE inhibitors and angiotensin II receptor antagonists should not be used simultaneously in patients with diabetic nephropathy.

Fluconazole, an inhibitor of the CYP2C9 isoenzyme, reduces plasma concentrations of the active metabolite and increases concentrations of losartan; however, the pharmacodynamic significance of this phenomenon has not been established. It has been shown that patients who do not metabolize Losartan to the active metabolite have a very rare and specific defect of the CYP2C9 isoenzyme.

Hydrochlorothiazide

The following drugs may interact with thiazide diuretics when used concomitantly.

Barbiturates, narcotic analgesics, ethanol – potentiation of the risk of orthostatic hypotension.

Hypoglycemic agents (oral and insulin) – dose adjustment of hypoglycemic agents may be required. Metformin should be used with caution due to the risk of lactic acidosis associated with possible renal failure caused by hydrochlorothiazide intake.

Other antihypertensive agents – an additive effect is possible.

Cholestyramine and colestipol reduce the absorption of hydrochlorothiazide. A single dose of cholestyramine or colestipol may reduce the absorption of hydrochlorothiazide from the gastrointestinal tract by 85% and 43%, respectively.

Corticosteroids, ACTH, laxatives, glycyrrhizic acid (contained in licorice root), amphotericin B (parenterally) – increased loss of electrolytes, exacerbation of hypokalemia.

Pressor amines (norepinephrine, epinephrine) – a slight reduction in the effect of pressor amines is possible, which does not preclude their use.

Non-depolarizing muscle relaxants (e.g., tubocurarine chloride) – potentiation of the effect of muscle relaxants is possible.

NSAIDs (including COX-2 inhibitors) – possible reduction of the diuretic, natriuretic, and antihypertensive effects of diuretics.

Lithium preparations – diuretics reduce the renal clearance of lithium and increase the risk of lithium intoxication, therefore concomitant use is not recommended.

Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol) – concomitant use with medicines for the treatment of gout may require dose adjustment of these drugs (increasing the dose of probenecid or sulfinpyrazone), since Hydrochlorothiazide may increase serum uric acid levels. Concomitant use of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g., atropine, biperiden) – increase the bioavailability of thiazide diuretics due to reduced gastrointestinal motility and gastric emptying rate.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate) – thiazide diuretics may reduce the renal excretion of cytotoxic drugs and potentiate their myelotoxic effects.

Salicylates – when salicylates are taken in high doses, Hydrochlorothiazide may enhance their toxic effect on the central nervous system.

Methyldopa – cases of hemolytic anemia have been reported with the concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine – concomitant use with cyclosporine may increase the risk of hyperuricemia and gout.

Cardiac glycosides – hypokalemia or hypomagnesemia caused by the use of thiazide diuretics may contribute to the development of arrhythmias when used concomitantly with cardiac glycosides.

Drugs affected by changes in serum potassium levels

Periodic monitoring of serum potassium levels and ECG is recommended when Losartan-H Richter is used concomitantly with drugs affected by changes in serum potassium levels (e.g., cardiac glycosides and antiarrhythmic drugs), as well as with the following agents (including antiarrhythmics) that can cause polymorphic ventricular tachycardia of the ‘torsades de pointes’ type, where hypokalemia is a predisposing factor for the development of polymorphic ventricular tachycardia of the ‘torsades de pointes’ type.

• Class IA antiarrhythmic drugs (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmic drugs (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Some antipsychotic drugs (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other drugs (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

Calcium salts – thiazide diuretics may increase serum calcium levels due to reduced excretion, so serum calcium levels should be monitored. If calcium supplements are necessary, the dose should be adjusted under the control of serum calcium levels.

Effect on laboratory test results – due to the effect of thiazide diuretics on calcium metabolism, their use may distort the results of parathyroid function tests.

Carbamazepine – increases the risk of symptomatic hyponatremia. Serum sodium levels should be monitored.

Iodinated contrast agents – in dehydration caused by diuretic intake, the risk of acute renal failure increases, especially with the simultaneous use of high doses of iodinated agents. Before administering such agents, the patient’s circulating blood volume should be replenished.

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 4 years. Do not use after the expiration date stated on the packaging.

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.