Cloart

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLOSART® (KLOSART®)

Composition:

Active substance: losartan;

1 tablet contains 25 mg, 50 mg, or 100 mg of losartan potassium;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide, Oparay O3B 52014 Yellow*.

*Oparay O3B 52014 Yellow: yellow iron oxide (E 172), quinoline yellow (E 104), hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, biconvex, film-coated tablets.

Pharmacotherapeutic group. Simple angiotensin II antagonists.

ATC code: C09CA01.

Pharmacological Properties

Pharmacodynamics

Losartan is a synthetic angiotensin II receptor antagonist (type AT1) for oral administration. Angiotensin II is a potent vasoconstrictor and the primary active hormone of the renin-angiotensin system, playing a key role in the pathophysiology of arterial hypertension. Angiotensin II binds to the AT1 receptor, found in many tissues (e.g., vascular smooth muscle, adrenal glands, kidneys, and heart), mediating several important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation.

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

Losartan exhibits neither agonistic nor antagonistic activity at other hormonal receptors or ion channels important in cardiovascular regulation. Moreover, losartan does not inhibit ACE (kininase II), the enzyme responsible for bradykinin breakdown. Therefore, bradykinin-mediated adverse effects are not potentiated.

During losartan administration, the removal of angiotensin II's negative feedback on renin secretion leads to increased plasma renin activity. This increase results in elevated plasma angiotensin II levels. Despite this rise, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and angiotensin II levels return to baseline values within 3 days.

Both losartan and its primary metabolite have higher affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10–40 times more potent than losartan (on a weight basis).

Pharmacokinetics

Absorption.

After oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming the active carboxylic acid metabolite and inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached at 1 hour and 3–4 hours, respectively.

Distribution.

Losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 L.

Biotransformation.

Approximately 14% of losartan is converted to the active metabolite following intravenous or oral administration. After intravenous or oral administration of radiolabeled 14C-losartan potassium, circulating plasma radioactivity is generally associated with losartan and its metabolites. Minimal conversion of losartan to its active metabolite occurs in approximately 1% of cases. In addition to the active metabolite, several inactive metabolites are formed.

Elimination.

Plasma clearance of losartan and its active metabolite is 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. After oral administration, about 4% of the dose is excreted unchanged in urine, and about 6% is excreted in urine as the active metabolite. The pharmacokinetic properties of losartan and its active metabolite are linear over oral doses up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with terminal half-lives of approximately 2 hours and 6–9 hours, respectively. At a dose of 100 mg once daily, neither losartan nor its active metabolite accumulates significantly in plasma. Losartan and its metabolites are excreted both via bile and urine. After oral administration/intravenous injection of 14C-labeled losartan, approximately 35%/43% of the radiolabeled drug was recovered in urine and 58%/50% in feces.

Special Patient Populations.

Elderly Patients.

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

Gender.

Plasma concentrations of losartan were twice as high in women with arterial hypertension compared to men, whereas plasma concentrations of the active metabolite did not differ significantly between men and women.

Hepatic and Renal Impairment.

Following oral administration to patients with mild to moderate alcoholic cirrhosis, plasma concentrations of losartan and its active metabolite were 5 times and 1.7 times higher, respectively, than in young male volunteers (see sections "Dosage and Administration" and "Special Precautions").

Plasma concentrations of losartan in patients with creatinine clearance above 10 mL/min do not differ from those in individuals with normal renal function. The area under the concentration-time curve (AUC) of losartan in patients with normal renal function was approximately twice that in patients undergoing hemodialysis. Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in those on hemodialysis. Neither losartan nor its active metabolite is removed by hemodialysis.

Pharmacokinetics in Children.

The active metabolite of losartan is formed in patients of all age groups. Pharmacokinetic parameters of losartan after oral administration were similar in neonates and children of preschool and school age.

Pharmacokinetic parameters of the metabolite varied more significantly depending on age group. These differences were statistically significant in preschool children and adolescents. Exposure in neonates and children under 2 years of age was relatively high.

Clinical characteristics.

Indications.

• Treatment of essential hypertension in adults and in children aged 6 years and older.
• Treatment of renal disease in adult patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day – as part of antihypertensive therapy (see sections "Pharmacological properties", "Contraindications", and "Special precautions").
• Treatment of chronic heart failure in adult patients when angiotensin-converting enzyme (ACE) inhibitors are considered unsuitable due to intolerance, particularly cough, or are contraindicated. Patients with heart failure whose condition has stabilized on an ACE inhibitor should not be switched to losartan therapy. The patient must have a left ventricular ejection fraction ≤ 40%, and the clinical condition must be stable. The patient should also be on established treatment for chronic heart failure.
• Reduction of the risk of stroke in adult patients with arterial hypertension and left ventricular hypertrophy confirmed by ECG.

Contraindications.

• Hypersensitivity to losartan or to any excipient of the medicinal product.
• Second and third trimesters of pregnancy (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
• Severe hepatic impairment.
• Concomitant use of losartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m² [see section "Interaction with other medicinal products and other forms of interaction"]).

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents may enhance the hypotensive effect of losartan. Concomitant use with other medicinal products that may cause hypotension as an adverse reaction (e.g., tricyclic antidepressants, antipsychotics, baclofen, and amifostine) may increase the risk of arterial hypotension.

Losartan is metabolized primarily by the cytochrome P450 (CYP) 2C9 system to its active carboxylic acid metabolite. Fluconazole (a CYP2C9 inhibitor) reduces exposure to the active metabolite by approximately 50%. Concomitant treatment with losartan and rifampicin (an enzyme inducer) has been shown to reduce plasma concentrations of the active metabolite by 40%. The clinical significance of this effect is unknown. There is no difference in exposure when losartan is used concomitantly with fluvastatin (a weak CYP2C9 inhibitor).

As with other medicinal products that block angiotensin II or its effects, concomitant use of agents that retain potassium in the body (e.g., potassium-sparing diuretics such as spironolactone, triamterene, amiloride), or that may increase potassium levels (e.g., heparin, trimethoprim-containing medicinal products), potassium supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such agents is not recommended.

When lithium preparations are used concomitantly with ACE inhibitors, there have been reports of reversible increases in serum lithium concentrations and lithium toxicity. Very rare cases of such interaction have also been reported with angiotensin II receptor blockers. Concomitant use of lithium and losartan requires caution. If such combination is considered necessary, monitoring of serum lithium levels during concomitant administration of these medicinal products is recommended.

When angiotensin II antagonists are used concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs; e.g., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, non-selective NSAIDs), the antihypertensive effect may be attenuated. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs may lead to an increased risk of worsening renal function, including possible development of acute renal failure, as well as increased serum potassium levels, particularly in patients with pre-existing renal impairment. Such combinations should be used with caution, especially in elderly patients. Adequate hydration should be maintained in patients,

and monitoring of renal function after initiation of concomitant therapy, as well as periodically during treatment, may be advisable.

Evidence indicates that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS (see sections "Contraindications" and "Special precautions").

Grapefruit juice contains components that inhibit CYP450 enzymes and may reduce the concentration of the active metabolite of losartan, potentially diminishing the therapeutic effect. Grapefruit juice should be avoided during treatment with tablets containing losartan.

Special precautions for use.

Hypersensitivity.

Angioedema.

Patients with a history of angioedema (facial, lip, throat, and/or tongue swelling) should be closely monitored (see section "Adverse reactions").

Arterial hypotension / fluid and electrolyte imbalance.

Symptomatic arterial hypotension, particularly after initiation or dose escalation of the medication, may occur in patients with reduced intravascular volume and/or sodium deficiency caused by potent diuretics, salt-restricted diet, diarrhea, or vomiting. Such conditions should be corrected prior to starting losartan therapy or require a reduced initial dose (see section "Dosage and administration"). These recommendations apply to children aged 6 to 18 years.

Electrolyte imbalance.

Electrolyte imbalances are frequently observed in patients with renal impairment (with or without diabetes mellitus) and should be taken into account. In a clinical trial involving patients with type II diabetes and nephropathy, hyperkalemia occurred more frequently with losartan than with placebo (see section "Adverse reactions"). Therefore, plasma potassium concentrations and creatinine clearance should be closely monitored, especially in patients with heart failure and creatinine clearance of 30–50 mL/min.

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., trimethoprim-containing drugs) with losartan is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hepatic impairment.

Since pharmacokinetic data indicate a significant increase in plasma losartan concentrations in patients with hepatic cirrhosis, dose reduction should be considered in patients with a history of hepatic dysfunction. There is no experience with losartan use in patients with severe hepatic impairment; therefore, losartan should not be administered to such patients (see sections "Dosage and administration", "Contraindications", and "Pharmacological properties").

Losartan is not recommended for use in children with hepatic impairment (see section "Special precautions for use").

Renal impairment.

Changes in renal function, including renal failure, have been reported and are associated with inhibition of the renin-angiotensin-aldosterone system (RAAS), particularly in patients whose renal function depends on RAAS activity (e.g., patients with severe heart failure or pre-existing renal impairment).

Medicinal products affecting the RAAS may increase blood urea nitrogen and serum creatinine levels in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney. These changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney.

Use in children with renal impairment

Losartan is not recommended for use in children with eGFR < 30 mL/min/1.73 m² due to lack of appropriate data (see section "Dosage and administration").

Renal function should be monitored regularly during losartan therapy, as deterioration may occur. This is particularly relevant when losartan is used in the presence of other conditions (e.g., fever, dehydration) that may affect renal function.

Concomitant use of losartan and ACE inhibitors may worsen renal function; therefore, this combination is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Kidney transplantation.

There is no experience regarding the safety of losartan use in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism generally do not respond to medicinal products acting via inhibition of the renin-angiotensin system. Therefore, losartan is not recommended for this patient group.

Coronary artery disease and cerebrovascular disease.

As with other antihypertensive medicinal products, excessive reduction in blood pressure in patients with ischemic coronary artery disease or cerebrovascular disease may lead to myocardial infarction or stroke.

Heart failure.

As with other medicinal products affecting the RAAS, patients with heart failure, with or without renal impairment, are at risk of developing severe arterial hypotension and (often acute) renal dysfunction.

There is insufficient therapeutic experience with losartan use in patients with heart failure and concomitant severe renal impairment, patients with severe heart failure (NYHA class IV), and patients with heart failure and symptomatic, life-threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patient groups. Concomitant use of losartan and β-blockers should be administered cautiously.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

As with other vasodilators, losartan should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Pregnancy.

Losartan therapy should not be initiated during pregnancy. In women planning pregnancy, losartan should be replaced with alternative antihypertensive agents with established safety profiles during pregnancy, unless continuation of losartan therapy is considered essential. Upon diagnosis of pregnancy, losartan should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Other warnings.

As observed with ACE inhibitors, losartan and other angiotensin antagonists may be less effective in patients of Black race compared to other patients, possibly due to lower renin activity in Black patients with hypertension.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute kidney injury). Therefore, dual RAAS blockade with combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual RAAS blockade is considered absolutely necessary, it should be performed under specialist supervision with close monitoring of renal function, electrolyte balance, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended in patients with diabetic nephropathy.

Intestinal angioedema.

Cases of intestinal angioedema have been reported in patients receiving angiotensin II receptor antagonists, including losartan (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, losartan must be discontinued and appropriate monitoring initiated until complete symptom resolution.

Excipients.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Losartan is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). Use of losartan is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. As there are no data from controlled epidemiological studies on the risk associated with angiotensin II receptor antagonists (ARBs), similar risks may apply to this class of medicinal products. Unless continuation of ARB therapy is considered essential, women planning pregnancy should be switched to alternative antihypertensive agents with a proven safety profile during pregnancy. Upon diagnosis of pregnancy, losartan should be discontinued immediately and alternative therapy initiated if necessary.

It is known that use of ARBs during the second and third trimesters of pregnancy in humans causes fetal toxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If losartan has been used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended.

Newborns whose mothers took losartan during pregnancy should be closely monitored for signs of arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Breastfeeding.

Due to lack of information on losartan use during breastfeeding, administration of this medicinal product is not recommended. An alternative treatment with a better-established safety profile during breastfeeding is preferred, especially during the neonatal period or if the infant is premature.

Ability to influence the speed of reactions while driving or operating machinery.

There are no data on the effect of losartan on the ability to drive or operate machinery. However, the possibility of adverse reactions such as dizziness and somnolence should be considered, particularly at the beginning of treatment and during dose escalation.

Method of Administration and Dosage.

Tablets can be taken regardless of food intake, swallowed with one glass of water.

Arterial hypertension.

The usual initial and maintenance dose for most patients is 50 mg of the drug once daily. Maximum antihypertensive effect is achieved within 3–6 weeks after initiation of therapy. For some patients, increasing the dose to 100 mg once daily (in the morning) may be beneficial.

Losartan may be used in combination with other antihypertensive drugs, particularly diuretics (e.g., hydrochlorothiazide) (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Patients with arterial hypertension and type 2 diabetes (proteinuria
≥ 0.5 g/day).

The usual initial dose is 50 mg once daily. The dose may be increased to 100 mg once daily depending on blood pressure levels one month after initiation of treatment. Losartan may be used concomitantly with other antihypertensive agents (e.g., diuretics, calcium channel blockers, α- or β-blockers, centrally acting agents) (see section "Special Warnings and Precautions for Use"), as well as with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones, and glucosidase inhibitors).

Heart failure.

The usual initial dose of losartan for patients with heart failure is 12.5 mg once daily. The dose should generally be titrated at weekly intervals (i.e., 12.5 mg daily, 25 mg daily, 50 mg daily, 100 mg daily) up to a maximum dose of 150 mg once daily, depending on patient tolerance.

Reduction of stroke risk in patients with arterial hypertension and left ventricular hypertrophy confirmed by ECG.

The usual initial dose is 50 mg of losartan once daily. Depending on blood pressure response, low-dose hydrochlorothiazide may be added and/or the dose of losartan may be increased to 100 mg once daily.

Special patient groups.

Use in patients with reduced blood volume.

In patients with reduced blood volume (e.g., due to high-dose diuretic therapy), consideration should be given to initiating treatment with a dose of 25 mg once daily.

Use in patients with renal impairment and patients undergoing hemodialysis.

No initial dose adjustment is required when administering losartan to patients with renal impairment or those undergoing hemodialysis.

Use in patients with hepatic impairment.

In patients with a history of hepatic impairment, a lower starting dose should be considered. There is no experience with treatment in patients with severe hepatic impairment; therefore, losartan is contraindicated in this patient group (see sections "Contraindications", "Special Warnings and Precautions for Use").

Children.

Use in children aged 6 months to 6 years.

The safety and efficacy of the drug in children aged 6 months to 6 years have not been established. Available data are presented in the section "Pharmacological Properties", but no dosage recommendations can be provided.

Use in children aged 6 to 18 years.

For children who can swallow tablets and whose body weight is greater than 20 kg but less than 50 kg, the recommended dose is 25 mg once daily. In exceptional cases, the dose may be increased to a maximum of 50 mg once daily. The dose should be adjusted based on its effect on blood pressure.

In patients with body weight greater than 50 kg, the usual dose is 50 mg once daily. In exceptional cases, the dose may be increased to a maximum of 100 mg once daily. Doses exceeding 1.4 mg/kg (or more than 100 mg) per day have not been studied in children.

Losartan is not recommended for use in children under 6 years of age due to insufficient data on use in this patient group.

Losartan is not recommended for use in children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of appropriate data (see section "Special Warnings and Precautions for Use").

Losartan is also not recommended for use in children with hepatic impairment.

Use in elderly patients.

Generally, no adjustment of the initial dose is required for elderly patients, although consideration should be given to initiating treatment with a dose of 25 mg in patients aged 75 years and older.

Children.

Losartan is not recommended for use in children under 6 years of age due to limited data in this patient group.

Overdose.

Symptoms.

Data on losartan overdose are limited. The most likely manifestations of overdose are arterial hypotension and tachycardia; bradycardia may result from parasympathetic (vagal) stimulation.

Treatment.

If symptomatic hypotension occurs, supportive therapy should be initiated.

Treatment depends on the time elapsed since drug ingestion and the nature and severity of symptoms.

The primary measure should be stabilization of cardiovascular function. After oral drug intake, administration of activated charcoal in an appropriate dose is indicated. Vital signs should be monitored frequently thereafter and corrected as necessary. Losartan and its active metabolites are not removed by hemodialysis.

Adverse Reactions

The most commonly reported adverse reaction was dizziness.

The frequency of the adverse reactions listed below is defined as follows: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10000 to <1/1000; very rare: <1/10000; not known (cannot be estimated from the available data).

Table.

Frequency of adverse reactions identified in placebo-controlled clinical studies and during post-marketing use of losartan

Adverse reaction	Frequency of adverse reactions in various indications				Other
	Arterial hypertension	Patients with arterial hypertension and left ventricular hypertrophy	Chronic heart failure	Arterial hypertension and type 2 diabetes with kidney disease	Post-marketing experience
From the blood and lymphatic system
anemia			common		frequency unknown
thrombocytopenia					frequency unknown
From the immune system
hypersensitivity reactions, anaphylactic reactions, angioedema* and vasculitis**					rare
From the psyche
depression					frequency unknown
From the nervous system
dizziness	common	common	common	common
drowsiness	uncommon
headache	uncommon		uncommon
sleep disturbance	uncommon
paraesthesia			rare
migraine					frequency unknown
dysgeusia					frequency unknown
From the ear and labyrinth
vertigo	common	common
tinnitus					frequency unknown
From the heart
palpitations	uncommon
angina pectoris	uncommon
syncope			rare
atrial fibrillation			rare
cerebrovascular event			rare
From the vascular system
(orthostatic) hypotension (including dose-dependent orthostatic effects) ║	uncommon		common	common
From the respiratory system, thorax and mediastinum
dyspnea			uncommon
cough			uncommon		frequency unknown
From the gastrointestinal tract
abdominal pain	uncommon
constipation	uncommon
diarrhea			uncommon		frequency unknown
nausea			uncommon
vomiting			uncommon
intestinal angioedema					rare
Hepatobiliary disorders
pancreatitis					frequency unknown
hepatitis					rare
liver function disorders					frequency unknown
From the skin and subcutaneous tissue
urticaria			uncommon		frequency unknown
pruritus			uncommon		frequency unknown
rash	uncommon		uncommon		frequency unknown
photosensitivity					frequency unknown
From the musculoskeletal and connective tissue
myalgia					frequency unknown
arthralgia					frequency unknown
rhabdomyolysis					frequency unknown
From the kidneys and urinary system
renal function impairment			common
renal failure			common
From the reproductive system and breast
erectile dysfunction/impotence					frequency unknown
General disorders and administration site conditions
general weakness	uncommon	common	uncommon	common
increased fatigue	uncommon	common	uncommon	common
edema	uncommon
malaise					frequency unknown
Investigations
hyperkalemia	common		uncommon†	common‡
increased alanine aminotransferase (ALT)§	rare
increased blood urea nitrogen, serum creatinine and serum potassium levels			common
hyponatremia					frequency unknown
hypoglycemia				common

* Including angioedema of the larynx, vocal cords, face, lips, pharynx, and/or tongue (causing airway obstruction); some of these patients had a history of angioedema with other medications, including ACE inhibitors.

** Includes Henoch-Schönlein purpura.

║Particularly in patients with intravascular hypovolemia, e.g., in patients with severe heart failure or those receiving high-dose diuretic therapy.

†This adverse reaction was more frequent in patients receiving 150 mg of losartan than in those receiving 50 mg.

‡In a clinical trial involving patients with type 2 diabetes and nephropathy, hyperkalemia (> 5.5 mmol/L) was observed in 9.9% of patients receiving losartan tablets and in 3.4% of patients receiving placebo.

§This adverse reaction usually resolved after discontinuation of losartan.

The following additional adverse reactions occurred more frequently in patients receiving losartan than in those receiving placebo (frequency unknown): back pain, urinary tract infections, and influenza-like symptoms.

Renal and urinary tract disorders.

In patients at increased risk, changes in renal function due to inhibition of the RAAS, including cases of renal failure, have been reported; these changes in renal function may be reversible upon discontinuation of the drug (see section "Special precautions").

Children.

The adverse reaction profile in children is similar to that in adult patients. Data on adverse reactions in children are limited.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug approval is highly important. It allows continuous monitoring of the benefit-risk ratio of the drug. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

Tablets 25 mg, 50 mg.

14 tablets in a blister; 1, 2, or 6 blisters in a cardboard box.

Tablets 100 mg.

14 tablets in a blister; 1, 2, or 6 blisters in a cardboard box.

10 tablets in a blister; 3, 9, or 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM" (for dosages 25 mg, 50 mg, 100 mg).

Manufacturer's location and address of business activity.

40020, Ukraine, Sumy Oblast, city of Sumy, Skryabina St., 54.

or

Manufacturer.

KUSUM HEALTHCARE PVT LTD/

KUSUM HEALTHCARE PVT LTD (for dosages 50 mg, 100 mg).

Manufacturer's location and address of business activity.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India/

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

or

Manufacturer.

LLC "GLEDPHARM LTD" (for dosages 25 mg, 50 mg, 100 mg).

Manufacturer's location and address of business activity.

40020, Ukraine, Sumy Oblast, city of Sumy, Davydovskoho Hryhoriia St., 54.