Losacor (Tablets) Instructions for Use

ATC Code

C09CA01 (Losartan)

Active Substance

Losartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Angiotensin II receptor antagonist

Pharmacological Action

Losacor is an antihypertensive drug, a specific antagonist of angiotensin II receptors (type AT1). Angiotensin II selectively binds to AT1 receptors located in many tissues (in vascular smooth muscle tissues, adrenal glands, kidneys, and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.

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 pathway of synthesis. Unlike some peptide angiotensin II antagonists, Losartan does not possess agonist effects. 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 the regulation of cardiovascular function.

Furthermore, Losartan does not inhibit ACE, which catalyzes the degradation of bradykinin. Consequently, effects not directly related to the blockade of AT1 receptors, in particular, the enhancement of effects associated with bradykinin exposure or angioedema (Losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

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 angiotensin II activity was observed at the time of reaching the maximum plasma concentration of the drug; in some patients, an even greater increase in losartan concentrations was observed, especially with a short duration of treatment (2 weeks). However, antihypertensive activity and a decrease in plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors.

After discontinuation of losartan, plasma renin activity and angiotensin II activity decreased to baseline values observed before the start of the drug administration after 3 days.

A study comparing the effects of 20 mg and 100 mg of losartan with the effects of an ACE inhibitor on the response to angiotensin I, angiotensin II, and bradykinin showed that Losartan blocks the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin, which is due to the specific mechanism of action of losartan.

In contrast, ACE inhibitors block the response to angiotensin I and increase the severity of the response to bradykinin, without affecting the severity of the response to angiotensin II, demonstrating a pharmacodynamic difference between losartan and ACE inhibitors.

The plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing drug dose. Since Losartan and its active metabolite are angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.

In a study with a single dose of 100 mg of losartan in healthy male volunteers, the use of the drug by patients on a salt-restricted diet and by patients consuming a lot of salt did not affect the glomerular filtration rate, effective renal plasma flow, and filtration fraction.

Losartan has a natriuretic effect, which was more pronounced with a low-salt diet and apparently was not associated with the suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in urinary uric acid excretion.

After a single oral administration, the hypotensive effect (systolic and diastolic blood pressure decreases) reaches a maximum after 6 hours, then gradually decreases over 24 hours. The maximum hypotensive effect develops 3-6 weeks after starting the drug. It stabilizes the plasma urea concentration. It does not affect autonomic reflexes and does not have a long-term effect on plasma norepinephrine concentration.

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

Pharmacokinetics

Absorption

When taken orally, Losartan is well absorbed from the gastrointestinal tract and undergoes a significant first-pass effect through the liver, resulting in the formation of an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan is approximately 33%. The mean C_max of losartan and its active metabolite is reached after 1 hour and after 3-4 hours, respectively. When taking losartan with a regular meal, no clinically significant effect on the plasma concentration profile of losartan was identified.

Distribution

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

Metabolism

Approximately 14% of the losartan dose (with oral and IV administration) is converted into its active metabolite. After oral or IV administration of ¹⁴C-labeled losartan, the radioactivity in the circulating plasma is primarily due to the presence of losartan and its active metabolite. Biologically inactive metabolites are also formed, including two main ones formed by hydroxylation of the butyl side chain, and one minor one – 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 unchanged by the kidneys and about 6% of the dose is excreted by the kidneys as the active metabolite. Losartan and its active metabolite have linear pharmacokinetics when 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 hours and 6-9 hours, respectively. With a single dose of the drug at a dose of 100 mg, neither Losartan nor its active metabolite accumulate significantly in the plasma.

Losartan and its metabolites are excreted through the intestines and kidneys. After oral administration of ¹⁴C-labeled losartan, about 35% of the radioactive label is found in the urine and 58% in the feces. After IV administration of ¹⁴C-labeled losartan, approximately 43% of the radioactive label is detected in the urine and 50% in the feces.

Pharmacokinetics in special patient groups

Plasma concentrations of losartan and its active metabolite in elderly patients with arterial hypertension do not differ significantly from these indicators in younger patients with arterial hypertension.

Plasma concentrations of losartan were 2 times higher in women with arterial hypertension compared to men with arterial hypertension. The concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference has no clinical significance.

After oral administration of losartan 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 healthy male volunteers.

Plasma concentrations of losartan in patients with creatinine clearance (CrCl) above 10 ml/min did not differ from those in individuals with normal renal function. In patients requiring hemodialysis, the AUC value is approximately 2 times higher than in patients with normal renal function. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite cannot be 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 reduction in the combined frequency of cardiovascular mortality, stroke, and myocardial infarction;
• Diabetic nephropathy with hypercreatininemia and proteinuria (urine albumin to creatinine ratio greater than 300 mg/g) in patients with type 2 diabetes and concomitant arterial hypertension (slowing the progression of diabetic nephropathy to end-stage chronic renal failure);
• Chronic heart failure when ACE inhibitor therapy is ineffective.

ICD codes

Dosage Regimen

Tablets

Orally, regardless of food intake, the tablets are swallowed without chewing, with water. Frequency of administration – once daily.

For arterial hypertension, the average daily dose is 50 mg once daily. In some cases, to achieve a greater effect, the dose is increased to 100 mg in 2 divided doses or once daily. The maximum dose is 100 mg/day. When prescribing the drug to patients receiving high doses of diuretics, the initial dose of the drug should be reduced to 25 mg (1/2 tab. of 50 mg) once daily.

There is no need to adjust the initial dose in elderly patients and in patients with renal failure, including patients on dialysis.

For patients with hepatic impairment (less than 9 points on the Child-Pugh scale), as well as for patients over 75 years of age, a lower initial dose of the drug is recommended – 25 mg (1/2 tab. of 50 mg) once daily.

There is insufficient experience with the use of the drug in patients with severe hepatic impairment, therefore the drug is not recommended for this category of patients.

For reducing the risk of cardiovascular diseases and mortality in patients with arterial hypertension and left ventricular hypertrophy, the usual initial dose is 50 mg once daily. Subsequently, hydrochlorothiazide in low doses may be added and/or the dose of Losacor may be increased to 100 mg per day in 1 or 2 divided doses.

For protecting renal function in patients with type 2 diabetes and proteinuria, the usual initial dose is 50 mg once daily. It is then recommended to increase the dose to 100 mg once daily, taking into account the degree of blood pressure reduction.

The initial dose for patients with heart failure is 12.5 mg once daily. As a rule, the dose is increased at weekly intervals (i.e., 12.5 mg/day, 25 mg/day, 50 mg/day) to an average maintenance dose of 50 mg once daily, depending on patient tolerance.

Adverse Reactions

Side effects by frequency of occurrence are distributed as follows: very common (≥10%), common (≥1%, but <10%), uncommon (≥0.1%, but <1%), rare (≥0.01%, but <0.1%), very rare (<0.01%), including isolated reports.

In patients with essential hypertension, the only side effect associated with taking the drug was dizziness, which was observed more often than with placebo and occurred in more than 1% of patients receiving Losacor. In addition, orthostatic reactions, dependent on the drug dose, were noted in less than 1% of patients. Rash was rarely reported, but its frequency of occurrence was less than with placebo.

Losacor was generally well tolerated by patients with left ventricular hypertrophy, patients with type 2 diabetes and proteinuria. The most common side effects associated with taking the drug were systemic and non-systemic dizziness, asthenia/weakness, pronounced decrease in blood pressure, hyperkalemia.

Side effects occurring with a frequency of more than 1%

General disorders abdominal pain 1.7% (placebo 1.7%), weakness and increased fatigue 3.8% (placebo 3.9%), chest pain 1.1% (placebo 2.6%), peripheral edema 1.7% (placebo 1.9%).

Cardiovascular system palpitations 1% (placebo 0.4%), tachycardia 1% (placebo 1.7%).

Digestive system diarrhea 1.9% (placebo 1.9%), dyspepsia 1.1% (placebo 1.5%), nausea 1.8% (placebo 2.8%).

Musculoskeletal system back pain 1.6% (placebo 1.1%), muscle cramps 1% (placebo 1.1%).

Central nervous system dizziness 4.1% (placebo 2.4%), headache 14.1% (placebo 17.2%), insomnia 1.1% (placebo 0.7%).

Respiratory system: cough 3.1% (placebo 2.6%), nasal mucosal edema 1.3% (placebo 1.1%), pharyngitis 1.5% (placebo 2.6%), sinusitis 1% (placebo 1.3%), upper respiratory tract infections 6.5% (placebo 5.6%).

Side effects occurring with a frequency of less than 1%

Allergic reactions angioedema, including edema of the larynx, glottis causing airway obstruction, and/or edema of the face, lips, pharynx and/or tongue.

Central nervous system migraine.

Musculoskeletal system myalgia, arthralgia.

Skin urticaria, skin itching.

Digestive system: hepatitis, impaired liver function.

Hematopoietic organs anemia, thrombocytopenia.

Respiratory system cough.

Laboratory parameters common – hyperkalemia (plasma potassium concentration more than 5.5 mEq/L); sometimes – increased concentration of urea and residual nitrogen or creatinine in blood serum; very rarely – moderate increase in the activity of liver transaminases (AST and ALT), hyperbilirubinemia.

In patients with dehydration (for example, those receiving treatment with high doses of diuretics), symptomatic arterial hypotension may occur at the beginning of treatment with losartan. In liver cirrhosis, the plasma concentration of losartan increases significantly.

In general, the drug is well tolerated, side effects are mild and transient and do not require drug withdrawal. The total frequency of side effects of Losacor is comparable to this indicator when taking placebo.

Contraindications

• Severe hepatic impairment (more than 9 points on the Child-Pugh scale);
• Lactose intolerance, lactase deficiency and glucose-galactose malabsorption;
• Pregnancy;
• Lactation period;
• Age under 18 years;
• Hypersensitivity to the components of the drug.

With caution arterial hypotension, reduced circulating blood volume, water-electrolyte balance disorders, bilateral renal artery stenosis or stenosis of the artery of a single kidney, renal failure, hepatic impairment (less than 9 points on the Child-Pugh scale); with simultaneous use with the following drugs (beta-blockers, sympatholytics, diuretics, hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, erythromycin, rifampin, fluconazole, lithium carbonate, potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements and salts containing potassium, NSAIDs, including selective COX-2 inhibitors).

Use in Pregnancy and Lactation

Losacor is contraindicated for use during pregnancy and lactation. It is known that drugs that directly affect the renin-angiotensin-aldosterone system (RAAS), when used in the II and III trimesters of pregnancy, can cause developmental defects or even death of the developing fetus. Therefore, if pregnancy is diagnosed, Losacor should be discontinued immediately.

It is not known whether Losartan is excreted in breast milk. It is not recommended to take Losacor during lactation. If it is necessary to take Losacor during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

With caution hepatic impairment (less than 9 points on the Child-Pugh scale).

Contraindicated

• Severe hepatic impairment (more than 9 points on the Child-Pugh scale).

For patients with hepatic impairment (less than 9 points on the Child-Pugh scale) – 25 mg (1/2 tab. of 50 mg) once daily.

Use in Renal Impairment

With caution bilateral renal artery stenosis or stenosis of the artery of a single kidney, renal failure.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

There is no need to adjust the initial dose in elderly patients.

For patients over 75 years of age a lower initial dose of the drug is recommended – 25 mg (1/2 tab. of 50 mg) once daily.

Special Precautions

Manifestation of such a symptom of hypersensitivity as angioedema is possible.

In patients with reduced osmotically active extracellular cation content (circulating blood volume) (for example, those receiving treatment with large doses of diuretics), symptomatic arterial hypotension may occur. Correction of such conditions should be carried out before prescribing Losacor or treatment should be started with a lower dose.

During treatment, blood potassium levels should be regularly monitored; especially in elderly patients, with impaired renal function.

Water-electrolyte imbalance is characteristic of patients with renal failure with or without diabetes, therefore, when prescribing the drug to this category of patients, special caution should be exercised.

In patients with liver cirrhosis, the plasma concentration of losartan increases significantly, therefore, if there is a history of liver disease, the drug should be prescribed in lower doses.

Drugs affecting the RAAS may increase blood urea and creatinine concentrations in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

During treatment, blood potassium levels should be regularly monitored, especially in elderly patients, with impaired renal function.

Effect on the ability to drive vehicles and operate machinery

No special clinical studies have been conducted to assess the effect of the drug on the ability to drive vehicles and work with machinery. The possibility of drowsiness and dizziness should be taken into account, therefore caution must be exercised when performing work requiring increased attention, especially at the beginning of treatment, when increasing the drug dose, and when driving vehicles.

Overdose

Information on overdose is limited.

Symptoms the most likely symptoms of overdose are pronounced decrease in blood pressure and tachycardia. Bradycardia may occur due to parasympathetic stimulation.

Treatment symptomatic therapy. Losartan and its active metabolite are not removed from the bloodstream by hemodialysis.

Drug Interactions

It mutually enhances the effects of beta-blockers and sympatholytics.

Concomitant use of losartan with diuretics has an additive effect.

No clinically significant interaction of the drug with such medicines as hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin was noted.

Rifampin and fluconazole decrease the concentration of the active metabolite. The clinical significance of these interactions has not been studied.

There is a report of lithium intoxication with concomitant use with lithium carbonate. When angiotensin II receptor antagonists and lithium are used concomitantly, an increase in plasma lithium concentration is possible. Considering this, the benefit and risk of concomitant use of losartan with lithium preparations should be weighed. If concomitant use of the drugs is necessary, plasma lithium concentration should be regularly monitored.

As with the use of other drugs that block the formation of angiotensin II and its effects, concomitant administration of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements and salts containing potassium may lead to an increase in serum potassium levels.

NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be weakened when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function who were treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of angiotensin II receptor antagonists may cause further deterioration of renal function. Usually this effect is reversible.

Storage Conditions

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

Shelf Life

Shelf life is 3 years.

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.