Losartan-Richter (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Poland, Co. Ltd. (Poland)

Or

Gedeon Richter-Rus, JSC (Russia)

Quality Control Release

GEDEON RICHTER POLAND, Co. Ltd. (Poland)

Or

GEDEON RICHTER-RUS, JSC (Russia)

Or

GEDEON RICHTER, Plc. (Hungary)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

C09CA01 (Losartan)

Active Substance

Losartan (Rec.INN registered by WHO)

Dosage Form

Losartan-Richter

Film-coated tablets, 50 mg: 10 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with a score on one side and an engraving “50” on the other.

Excipients: colloidal silicon dioxide, magnesium stearate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose.

Film coating composition Opadry II 33G28523 (triacetin, macrogol, lactose monohydrate, titanium dioxide (E171, C.I.77891), hypromellose).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Angiotensin II receptor antagonist

Pharmacological Action

Mechanism of action

Angiotensin II is a potent vasoconstrictor, the primary active hormone of the 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. Furthermore, angiotensin II stimulates the proliferation of smooth muscle cells. AT₂ receptors are a second type of receptor to which angiotensin II binds, but their role in regulating cardiovascular function is unknown.

Losartan is a selective antagonist of angiotensin II AT₁ receptors, highly effective when administered orally. Losartan and its pharmacologically active carboxylated metabolite (E-3174) block all physiological effects of angiotensin II, regardless of its source or synthesis pathway, both in vitro and in vivo. Unlike some peptide angiotensin II antagonists, Losartan does not possess agonist properties.

Losartan selectively binds to AT₁ receptors and does not bind to or block receptors of other hormones and ion channels that play an important role in regulating cardiovascular function. Furthermore, Losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), which is responsible for the breakdown of bradykinin. Consequently, effects not directly related to the blockade of AT₁ receptors, such as potentiation of bradykinin-mediated effects or the development of edema (Losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Pharmacodynamics

Losartan inhibits the increase in systolic and diastolic blood pressure (BP) induced by angiotensin II infusion. At the time of reaching C_max of losartan in plasma after a 100 mg dose, the aforementioned effect of angiotensin II is suppressed by approximately 85%, and 24 hours after a single or multiple doses, by 26-39%.

During losartan administration, the elimination of negative feedback, consisting of the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (PRA). The increase in PRA leads to an increase in plasma angiotensin II concentration. During long-term (6-week) treatment of patients with arterial hypertension with losartan at a dose of 100 mg/day, a 2-3-fold increase in plasma angiotensin II concentration was observed at the time of reaching C_max of losartan. In some patients, an even greater increase in angiotensin II concentration was observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, the antihypertensive effect and the decrease in plasma aldosterone concentration were evident at 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, PRA and angiotensin II concentration decreased within 3 days to values observed before starting losartan. Since Losartan is a specific antagonist of angiotensin II AT₁ receptors, it does not inhibit ACE (kininase II) – the enzyme that inactivates bradykinin.

Plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing drug dose. Because Losartan and its active metabolite are angiotensin II receptor antagonists (ARBs), they both contribute to the antihypertensive effect.

Oral administration under high- and low-salt diet conditions did not affect glomerular filtration rate (GFR), effective renal plasma flow, and filtration fraction. Losartan had a natriuretic effect, which was more pronounced with a low-salt diet and apparently not associated with suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in urinary uric acid excretion.

In patients with arterial hypertension, proteinuria (at least 2 g/24 h), without diabetes mellitus, and taking Losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, a significant reduction in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG) was observed. In these patients, Losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with arterial hypertension taking Losartan at a dose of 50 mg for 4 weeks, no effect of therapy on renal and systemic prostaglandin levels was detected.

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

In patients with arterial hypertension, Losartan in doses up to 150 mg/day did not cause clinically significant changes in fasting triglyceride concentrations, total cholesterol, and HDL cholesterol. At the same doses, Losartan did not affect fasting blood glucose concentration.

Overall, Losartan caused a decrease in serum uric acid concentration (usually less than 0.4 mg/dl), which persisted during long-term treatment.

Losartan at a dose of 150 mg/day significantly reduced the risk of all-cause mortality or hospitalization for heart failure compared to a dose of 50 mg/day (hazard ratio [HR] 0.899, p=0.027).

Losartan increased cardiac index and reduced pulmonary capillary wedge pressure, and also reduced systemic vascular resistance, mean systemic BP, and heart rate. The incidence of arterial hypotension was dose-dependent.

Pharmacokinetics

Absorption

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

Distribution

Losartan and its active metabolite are bound to plasma proteins (mainly albumin) by at least 99%. The V_d of losartan is 34 L. Preclinical studies have shown that Losartan practically does not cross the BBB.

Metabolism

Approximately 14% of the losartan dose after IV administration or oral intake is converted to its active metabolite. After oral or IV 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. In addition to the active metabolite, biologically inactive metabolites are formed, including two main metabolites formed by hydroxylation of the butyl side chain and one minor metabolite – N-2-tetrazole glucuronide.

Excretion

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 by the kidneys as the active metabolite. Losartan and its active metabolite have linear pharmacokinetics when losartan is taken orally in doses up to 200 mg. After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal T_1/2 of approximately 2 and 6-9 hours, respectively. With a dosing regimen of 100 mg once daily, no significant accumulation of losartan and its active metabolite occurs in plasma. Losartan and its metabolites are excreted by the kidneys and through the intestine with bile. After oral administration of ¹⁴C losartan in men, about 35% of radioactivity is found in urine and 58% in feces. After IV administration of ¹⁴C losartan in men, approximately 43% of radioactivity is found in urine and 50% in feces.

Pharmacokinetics in special patient groups

Plasma concentrations of losartan and its active metabolite in elderly male patients (over 65 years) with arterial hypertension do not differ significantly from these indicators in young male patients with arterial hypertension.

Plasma losartan concentration values in women with arterial hypertension were 2 times higher than the corresponding values in men with arterial hypertension. Concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference, however, has no clinical significance.

When losartan was taken orally by 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 healthy male volunteers.

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 impaired renal function or patients on hemodialysis. Losartan and its active metabolite are not removed by hemodialysis.

Indications

• Arterial hypertension;
• Reduction of associated cardiovascular morbidity and mortality risk in patients with arterial hypertension and left ventricular hypertrophy, manifested by a combined reduction in cardiovascular mortality, stroke, and myocardial infarction incidence;
• Chronic kidney disease in patients with arterial hypertension and type 2 diabetes mellitus with concomitant proteinuria ≥0.5 g/day as an antihypertensive agent as part of combination therapy;
• Chronic heart failure in case of ineffectiveness of ACE inhibitor treatment or intolerance to ACE inhibitors. It is not recommended to switch patients with chronic heart failure and stable parameters while taking ACE inhibitors to losartan therapy.

ICD codes

Dosage Regimen

The drug is taken orally regardless of meals. Losartan-Richter can be taken in combination with other antihypertensive agents.

Arterial hypertension

The standard initial and maintenance dose for most patients is 50 mg once daily. The maximum antihypertensive effect is achieved within 3-6 weeks from the start of therapy. In some patients, to achieve a greater effect, the dose can be increased to a maximum daily dose of 100 mg once daily.

In patients with reduced blood volume (e.g., when taking diuretics in high doses), the initial dose of losartan should be reduced to 25 mg (half a 50 mg tablet) once daily.

No initial dose adjustment is necessary for elderly patients and patients with impaired renal function (including patients on dialysis).

Patients with a history of liver disease are recommended to be prescribed the drug at lower doses.

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

The standard initial dose of the drug is 50 mg once daily. Subsequently, it is recommended to add hydrochlorothiazide in low doses or increase the dose of Losartan-Richter to the maximum daily dose of 100 mg once daily, taking into account the degree of BP reduction.

Chronic kidney disease in patients with arterial hypertension and type 2 diabetes mellitus with concomitant proteinuria

The standard initial dose of the drug is 50 mg once daily. Subsequently, the dose of Losartan-Richter can be increased to the maximum daily dose of 100 mg once daily, taking into account the degree of BP reduction.

Losartan-Richter can be prescribed in combination with other antihypertensive agents (e.g., diuretics, calcium channel blockers, alpha- and beta-blockers, centrally acting antihypertensive agents), insulin and other hypoglycemic agents (e.g., sulfonylurea derivatives, glitazones, and glucosidase inhibitors).

Chronic heart failure (CHF)

The initial dose of losartan for patients with CHF is 12.5 mg once daily (when prescribing losartan in low doses, it must be taken into account that Losartan-Richter in a dosage of 12.5 mg is not available on the Russian market; it is necessary to use other losartan potassium preparations available on the Russian market in a dosage of 12.5 mg). Typically, the dose is titrated at weekly intervals (i.e., 12.5 mg/day, 25 mg/day, 50 mg/day, 100 mg/day up to the maximum (only for this indication) dose of 150 mg once daily) depending on individual tolerance.

Adverse Reactions

Adverse events (AEs) listed below were observed during clinical studies. The frequency of AEs is given according to the following classification: very common – 1/10 administrations (≥10%), common – 1/100 administrations (≥1%, but <10%), uncommon - 1/1000 administrations (≥0.1%, but <1%), rare - 1/10,000 administrations (≥0.01%, but <0.1%), very rare - less than 1/10,000 administrations (<0.01%), frequency unknown - insufficient data to estimate frequency.

Within each group, adverse reactions are listed in order of decreasing significance.

Patients with arterial hypertension

Nervous system disorders common – dizziness; uncommon – drowsiness, headache, sleep disorders.

Ear and labyrinth disorders common – systemic dizziness (vertigo).

Cardiac and vascular disorders uncommon – palpitations, angina pectoris, (orthostatic) hypotension (including dose-mediated orthostatic effects, especially in patients with reduced blood volume, e.g., patients with severe heart failure or patients receiving high-dose diuretic therapy).

Gastrointestinal disorders uncommon – abdominal pain, constipation.

Skin and subcutaneous tissue disorders uncommon – skin rash.

General disorders and administration site conditions uncommon – asthenia, increased fatigue, edema.

Laboratory and instrumental data common – hyperkalemia; rare – increased ALT activity (usually returned to normal after discontinuation of therapy).

Patients with arterial hypertension and left ventricular hypertrophy

Nervous system disorders common – dizziness.

Ear and labyrinth disorders common – systemic dizziness (vertigo).

General disorders and administration site conditions uncommon – asthenia, increased fatigue.

Patients with type 2 diabetes mellitus and proteinuria

Nervous system disorders common – dizziness.

Cardiac and vascular disorders common – hypotension (orthostatic, including dose-mediated orthostatic effects, especially in patients with reduced blood volume, e.g., patients with severe heart failure or patients receiving high-dose diuretic therapy).

General disorders and administration site conditions uncommon – asthenia, increased fatigue.

Laboratory and instrumental data common – hyperkalemia, hypoglycemia.

Patients with chronic heart failure

Blood and lymphatic system disorders common – anemia.

Nervous system disorders common – dizziness; uncommon – headache; rare – paresthesia.

Cardiac and vascular disorders common – hypotension (orthostatic, including dose-mediated orthostatic effects, especially in patients with reduced blood volume, e.g., patients with severe heart failure or patients receiving high-dose diuretic therapy); rare – syncope, atrial fibrillation, cerebrovascular disorder.

Respiratory system disorders infrequent – dyspnea, cough.

Gastrointestinal system disorders infrequent – diarrhea, nausea, vomiting.

Skin and subcutaneous tissue disorders infrequent – urticaria, pruritus, skin rash.

Renal and urinary disorders frequent – impaired renal function, renal failure.

General disorders and administration site conditions infrequent – asthenia, increased fatigue.

Investigations frequent – increased blood creatinine, urea and potassium concentrations; infrequent – hyperkalemia (more often in patients taking Losartan 150 mg/day than in patients taking Losartan 50 mg/day).

Adverse reactions observed in clinical practice during the post-marketing period

Blood and lymphatic system disorders frequency unknown – anemia, thrombocytopenia.

Immune system disorders rare – hypersensitivity reactions, anaphylactic reactions, angioedema, including laryngeal, pharyngeal, facial, lip, pharyngeal and/or tongue edema causing airway obstruction; some of these patients had a history of angioedema with other drugs (including ACE inhibitors), vasculitis (including Henoch-Schönlein purpura).

Psychiatric disorders frequency unknown – depression.

Nervous system disorders frequency unknown – migraine, dysgeusia.

Ear and labyrinth disorders frequency unknown – tinnitus.

Respiratory system disorders frequency unknown – cough.

Gastrointestinal system disorders frequency unknown – diarrhea, pancreatitis.

Hepatobiliary disorders rare – hepatitis; frequency unknown – impaired liver function.

Skin and subcutaneous tissue disorders frequency unknown – urticaria, pruritus, rash, photosensitivity.

Musculoskeletal and connective tissue disorders frequency unknown – myalgia, arthralgia, rhabdomyolysis.

Reproductive system and breast disorders frequency unknown – erectile dysfunction/impotence.

General disorders and administration site conditions frequency unknown – malaise.

Investigations frequency unknown – hyponatremia.

Contraindications

• Severe hepatic impairment (no experience of use);
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety have not been established);
• Concomitant use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with ACE inhibitors in patients with diabetic nephropathy;
• Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Hypersensitivity to the active substance or to any of the excipients of the drug.

With caution bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; hyperkalemia; conditions after kidney transplantation (no experience of use); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; chronic heart failure with concomitant severe renal impairment; severe chronic 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; water-electrolyte imbalance; hepatic impairment; renal impairment; patients with reduced circulating blood volume (e.g., those receiving high-dose diuretic therapy) – symptomatic arterial hypotension may occur.

Use in Pregnancy and Lactation

Pregnancy

Drugs that act directly on the RAAS can cause serious damage and death to the developing fetus, so if pregnancy is diagnosed, Losartan-Richter should be discontinued immediately and, if necessary, alternative antihypertensive therapy should be prescribed.

Therapy with Losartan-Richter should not be initiated during pregnancy. If continuation of losartan therapy is considered necessary for patients planning pregnancy, Losartan should be replaced with alternative antihypertensive agents that have an established safety profile for use during pregnancy.

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

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

The use of drugs affecting the RAAS in the second and third trimesters 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 described above are usually due to the use of drugs affecting the RAAS in the second and third trimesters 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 agents. 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 should be performed to assess the intra-amniotic space. If oligohydramnios is detected, Losartan-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. Careful monitoring of newborns whose mothers took Losartan-Richter during pregnancy is necessary to monitor arterial hypotension, oliguria and hyperkalemia.

Breastfeeding period

It is not known whether Losartan passes into breast milk. Since many drugs pass into 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 its use for the mother.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment (no experience of use).

With caution – in hepatic impairment.

Use in Renal Impairment

Use with caution in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; conditions after kidney transplantation (no experience of use); in renal impairment.

Pediatric Use

Contraindicated in children under 18 years of age (efficacy and safety have not been established).

Geriatric Use

Clinical studies have not revealed any specific features regarding the safety and efficacy of losartan in elderly patients (over 65 years of age).

Special Precautions

Hypersensitivity reactions

When using the drug in patients with a history of angioedema (swelling of the face, lips, pharynx/larynx and/or tongue), careful monitoring is necessary.

Arterial hypotension and water-electrolyte imbalance or reduced circulating blood volume

Symptomatic arterial hypotension may occur in patients with reduced circulating blood volume (e.g., those receiving high-dose diuretic therapy). Correction of such conditions should be carried out before prescribing losartan or treatment should be started with a lower dose of losartan.

Water-electrolyte imbalance is characteristic of patients with renal impairment with or without diabetes mellitus, so careful monitoring of these patients is necessary. In clinical studies involving patients with type 2 diabetes mellitus with proteinuria, the number of cases of hyperkalemia was greater in the group taking Losartan than in the group taking placebo. Several patients discontinued therapy due to hyperkalemia.

During treatment with losartan, it is not recommended to take potassium-sparing diuretics, potassium preparations or potassium-containing salt substitutes.

Aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy

Like all drugs with vasodilating action, ARBs should be used with particular caution in patients with mitral stenosis, aortic stenosis or hypertrophic obstructive cardiomyopathy.

Coronary artery disease and cerebrovascular diseases

Like all drugs with vasodilating action, ARBs should be prescribed with caution to patients with coronary artery disease or cerebrovascular diseases, since an excessive decrease in blood pressure in this group of patients can lead to the development of myocardial infarction or stroke.

Chronic heart failure

As with the use of other drugs that affect the RAAS, in patients with CHF and with or without renal impairment, there is a risk of developing severe arterial hypotension or acute renal impairment. Since there is insufficient experience with the use of losartan in patients with CHF and concomitant severe renal impairment, in patients with severe CHF (NYHA functional class IV), as well as in patients with CHF and symptomatic life-threatening arrhythmias, Losartan should be used with caution in these groups of patients.

Hepatic impairment

Data from pharmacokinetic studies indicate that the plasma concentration of losartan is significantly increased in patients with liver cirrhosis, so patients with a history of hepatic impairment should be prescribed Losartan at a lower dose. There is no experience with the use of losartan in patients with severe hepatic impairment, so the drug should not be used in this group of patients.

Renal impairment

Due to inhibition of the RAAS, changes in renal function, including the development of renal failure, have been observed in some predisposed patients. These changes in renal function may return to normal after discontinuation of treatment.

Some drugs that affect the RAAS may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney. Similar effects have been reported with losartan. Such renal function impairments may be reversible after discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney.

Kidney transplantation

There are no data on the use of losartan preparations in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Since patients with primary hyperaldosteronism usually do not respond positively to antihypertensive therapy that acts by inhibiting the RAAS, the use of losartan is not recommended in this group of patients.

Ethnic differences

Like ACE inhibitors, Losartan and other ARBs have a less pronounced antihypertensive effect in Black patients compared to other races, which may be due to the higher prevalence of conditions with low plasma renin activity in Black patients with arterial hypertension. Analysis of data from the entire patient population included in the LIFE study on the effect of losartan on reducing the incidence of the primary composite endpoint in patients with arterial hypertension and left ventricular hypertrophy (n=9193) showed that the ability of losartan compared with atenolol to reduce the risk of stroke and myocardial infarction, as well as to reduce the cardiovascular mortality rate in patients with arterial hypertension and left ventricular hypertrophy (by 13.0%, p=0.021) does not extend to Black patients, although both treatment regimens effectively reduced blood pressure in these patients. In this study, Losartan compared with atenolol reduced the cardiovascular morbidity and mortality rate in patients with arterial hypertension and left ventricular hypertrophy of all races except Black (n=8660, p=0.003). However, in this study, Black patients receiving atenolol had a lower risk of developing the primary composite endpoint (i.e., a lower combined incidence of cardiovascular mortality, stroke and myocardial infarction) compared with patients of the same race taking Losartan (p=0.03).

Elderly patients (over 65 years of age)

Clinical studies have not revealed any specific features regarding the safety and efficacy of losartan in elderly patients (over 65 years of age).

Children and adolescents under 18 years of age

The efficacy and safety of losartan in children and adolescents under 18 years of age have not been established.

If newborns whose mothers took Losartan during pregnancy develop oliguria or arterial hypotension, symptomatic therapy aimed at maintaining blood pressure and renal perfusion should be carried out. Blood transfusion or dialysis may be required to prevent arterial hypotension and/or maintain renal function.

Embryo-fetal toxicity

The use of drugs affecting the RAAS in the second and third trimesters 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. If pregnancy is detected, Losartan should be discontinued immediately.

Dual blockade of the RAAS

Arterial hypotension, syncope, stroke, hyperkalemia and renal function impairments (including acute renal failure) have been reported in susceptible patients, especially if combination therapy with drugs affecting the RAAS is used.

Concomitant use of ARBs (including losartan) with aliskiren and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or 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 ARBs (including losartan) with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

In cases where the simultaneous prescription of two drugs affecting the RAAS is absolutely necessary, their use should be carried out under medical supervision with particular caution and with regular monitoring of renal function, blood pressure and plasma electrolyte levels.

Lactose

In case of lactose intolerance, it should be taken into account that 1 tablet of Losartan-Richter 50 mg contains 1.05 mg of lactose monohydrate, and a 100 mg tablet contains 2.10 mg of lactose monohydrate. In this regard, patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption are not recommended to take this drug.

Effect on ability to drive vehicles and operate machinery

No studies have been conducted to assess the effect on the ability to drive vehicles and operate machinery, but caution should be exercised when using antihypertensive therapy and driving vehicles or operating machinery, since dizziness and drowsiness may develop, especially at the beginning of therapy or when increasing the dose.

Overdose

Information on overdose is limited.

Symptoms the most likely manifestation of overdose is a pronounced decrease in blood pressure and tachycardia; bradycardia may occur due to parasympathetic (vagal) stimulation.

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

Drug Interactions

Pharmacodynamic interactions

Dual blockade of the RAAS

Dual blockade of the RAAS with the use of ARBs, ACE inhibitors or aliskiren (a renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and renal function impairments (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, renal function and blood electrolyte levels is necessary in patients taking Losartan and other drugs affecting the RAAS simultaneously.

Concomitant use of losartan with aliskiren or aliskiren-containing drugs is contraindicated in patients with diabetes mellitus and/or 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 antihypertensive drugs

Antihypertensive agents may increase the antihypertensive effect of losartan. Enhancement of the antihypertensive effect of losartan and an increased risk of arterial hypotension are also possible with the concomitant use of other drugs that lower blood pressure as a primary or side effect (such as tricyclic antidepressants, antipsychotics, baclofen, amifostine).

Drugs that increase blood potassium levels

Concomitant use of losartan (like other drugs that block angiotensin II or its effects) with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes and other drugs that can increase serum potassium levels (including heparin) may lead to an increase in serum potassium levels.

NSAIDs

NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors and acetylsalicylic acid in high doses (≥3 g/day), may reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of ARBs or ACE inhibitors may be weakened when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

In some patients with pre-existing renal impairment (for example, elderly patients or patients with dehydration, including those taking diuretics), receiving NSAID therapy (including selective COX-2 inhibitors), the concomitant use of ARBs or ACE inhibitors may cause further deterioration of renal function, including the development of acute renal failure, and hyperkalemia. These effects are usually reversible.

Concomitant use of ARBs and NSAIDs should be carried out with caution (especially in elderly patients and in patients with impaired renal function). Patients should receive an adequate amount of fluid. It is recommended to carefully monitor renal function, both at the beginning and during treatment.

Lithium preparations

Like ACE inhibitors and other drugs affecting sodium excretion, Losartan may reduce the renal excretion of lithium and lead to an increase in its toxic effects. Therefore, with the simultaneous use of lithium preparations and ARBs, it is necessary to carefully monitor the serum lithium concentration.

Pharmacokinetic interaction

In clinical studies of the pharmacokinetic interaction of drugs, no clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, and phenobarbital were identified.

Rifampicin

Rifampicin, which is an inducer of drug metabolism, reduces the plasma concentration of the active metabolite of losartan by 40%.

CYP3A4 inhibitors

The use of two CYP3A4 isoenzyme inhibitors, ketoconazole and erythromycin, was studied in clinical trials. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect when losartan was taken orally.

CYP2C9 inhibitors

It has been shown that in patients who do not metabolize Losartan to the active metabolite, there is a very rare and specific defect of the CYP2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is carried out predominantly by the CYP2C9 isoenzyme.

Fluconazole, an inhibitor of the CYP2C9 isoenzyme, reduces the concentration of the active metabolite of losartan by approximately 50%. No changes in losartan exposure were detected when it was taken concomitantly with fluvastatin (a weak inhibitor of the CYP2C9 isoenzyme). The clinical significance of changes in the pharmacokinetics of losartan during its concomitant use with CYP2C9 isoenzyme inhibitors is unknown.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 5 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.