Losartan-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOSARTAN-TEVA (LOSARTAN-TEVA)

Composition:

Active substance: losartan potassium;

1 tablet contains 12.5 mg, or 25 mg, or 50 mg, or 100 mg of losartan potassium;

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (corn), magnesium stearate, partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

12.5 mg tablets: white, round, slightly convex film-coated tablets, embossed with "L" on one side and smooth on the other;

25 mg tablets: white, oval, slightly convex film-coated tablets, embossed with "2", a division line, and "5" on one side and a division line on the other;

50 mg tablets: white, oval, slightly convex film-coated tablets, embossed with "50" on one side and a division line on the other;

100 mg tablets: white, oval, slightly convex film-coated tablets, embossed with "100" on one side and a division line on the other.

Pharmacotherapeutic group. Simple angiotensin II receptor antagonists. ATC code: C09CA01.

Pharmacological Properties

Pharmacodynamics

Losartan is a synthetic oral angiotensin II receptor antagonist (type AT1). 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, located 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 binds to the AT1 receptor. Both in vitro and in vivo, losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block all significant physiological effects of angiotensin II, regardless of the source or pathway of its synthesis.

Losartan does not bind to or block other hormone receptors or ion channels important for cardiovascular regulation. Losartan does not inhibit angiotensin-converting enzyme (ACE) (kininase II), the enzyme responsible for bradykinin degradation. Therefore, it does not enhance bradykinin-mediated adverse reactions.

During losartan treatment, the removal of angiotensin II’s negative feedback on renin secretion increases plasma renin activity (PRA). This increase in PRA leads to 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 plasma angiotensin II levels return to baseline within 3 days.

Both losartan and its primary metabolite have higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10 to 40 times more potent than losartan.

Clinical studies have shown that combining ACE inhibitors with angiotensin II receptor antagonists in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with target organ damage provides no significant additional benefit on renal or cardiovascular function or mortality compared to monotherapy. However, combination therapy is associated with an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension. Therefore, concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

A study evaluating the combination of aliskiren with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease was terminated early due to a high risk of adverse outcomes. Stroke and cardiovascular mortality occurred more frequently in the aliskiren group compared to placebo. Additionally, adverse events and serious adverse reactions, such as hyperkalemia, arterial hypotension, and renal dysfunction, were more common in patients receiving aliskiren than in the placebo group.

Pharmacokinetics

Absorption

After oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an 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 approximately 1 hour and 3–4 hours, respectively.

Distribution

Over 99% of losartan and its active metabolite are protein-bound in plasma, primarily to albumin. The volume of distribution of losartan is 34 liters.

Biological Transformation

Approximately 14% of losartan is converted to its active metabolite following intravenous administration or oral intake. After intravenous or oral administration of radiolabeled 14C-losartan potassium, circulating plasma radioactivity is primarily associated with losartan and its metabolite. Minimal conversion of losartan to its active metabolite occurs in approximately 1% of cases. In addition to the active metabolite, inactive metabolites are also 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, approximately 4% of the dose is excreted unchanged in urine and about 6% as the active metabolite. The pharmacokinetic properties of losartan and its active metabolite are linear following oral doses of losartan potassium up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with terminal elimination 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 via both bile and urine. After oral administration/intravenous injection of 14C-labeled losartan, approximately 35%/43% of the radiolabeled dose was recovered in urine and 58%/50% in feces.

Special Patient Populations

Elderly Patients. Plasma concentrations of losartan and its active metabolite in elderly hypertensive patients do not differ significantly from those in younger hypertensive patients.

Gender. Plasma concentrations of losartan are approximately twice as high in women with hypertension compared to men, whereas plasma concentrations of the active metabolite do not differ significantly between men and women.

Hepatic and Renal Impairment. Following oral administration, plasma concentrations of losartan and its active metabolite in patients with mild to moderate alcoholic cirrhosis are approximately 5 times and 1.7 times higher, respectively, than in young male volunteers.

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 undergoing hemodialysis is approximately twice that observed in patients with normal renal function.

Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in those undergoing hemodialysis.

Losartan and its active metabolite cannot be removed by hemodialysis.

Pharmacokinetics in Children

The pharmacokinetics of losartan were studied in 50 children with arterial hypertension aged 1 month to 16 years, following once-daily oral administration at doses ranging from 0.54 mg/kg to 0.77 mg/kg (mean doses).

Results showed that the active metabolite of losartan is formed in patients across all age groups. Pharmacokinetic parameters of losartan after oral administration were similar in neonates, preschool, and school-aged children.

Metabolite pharmacokinetic parameters showed greater variability depending on age group. These differences were statistically significant in preschool children and adolescents. Exposure was relatively high in neonates and young children.

Clinical characteristics.

Indications.

• Treatment of essential arterial hypertension in adults, as well as in children aged 6 years and older.
• Treatment of kidney disease in adult patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥0.5 g per day – as part of combined antihypertensive therapy.
• Treatment of chronic heart failure in adults when the use of angiotensin-converting enzyme (ACE) inhibitors is considered impossible due to intolerance, particularly cough, or is contraindicated. Patients with heart failure whose condition has been stabilized on an ACE inhibitor should not be switched to losartan therapy. The patient must have a left ventricular ejection fraction ≤40%, a clinically stable condition, and should be receiving 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 the active substance or to any of the excipients of the medicinal product.

Pregnancy or planned pregnancy (see section "Use in pregnancy or breast-feeding").

Severe hepatic impairment.

Concomitant use of losartan with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 mL/min/1.73 m²).

Breast-feeding.

Children under 6 years of age.

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents may enhance the hypotensive effect of losartan. Agents that may cause arterial hypotension include tricyclic antidepressants, antipsychotic agents, baclofen, and amifostine. Concomitant use of these agents with antihypertensive drugs increases the risk of arterial hypotension. Losartan is metabolized primarily via the cytochrome P450 (CYP) 2C9 system, forming an active carboxylic acid metabolite. Fluconazole (a CYP2C9 inhibitor) has been reported to reduce exposure to the active metabolite by approximately 50%. Concomitant use of 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 agents that block angiotensin II or its effects, concomitant use of drugs that retain potassium in the body (e.g., potassium-sparing diuretics such as spironolactone, triamterene, amiloride) or that may increase serum potassium levels (such as heparin, trimethoprim-containing preparations), potassium supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such medicinal products is not recommended.

Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Such effects have also very rarely been reported with angiotensin II receptor antagonists. Concomitant treatment with lithium and losartan should be undertaken with caution. If use of this combination is considered necessary, monitoring of serum lithium levels during combination therapy is recommended.

Concomitant use of angiotensin II receptor antagonists and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, non-selective NSAIDs) may attenuate the antihypertensive effect. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs increases the risk of worsening renal function, including acute renal failure, as well as hyperkalemia, particularly in patients with pre-existing renal impairment. Such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function after initiation of concomitant therapy and periodically during treatment may be advisable.

Clinical trial data have shown 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 reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS.

Grapefruit juice contains components that inhibit CYP450 enzymes and may reduce the concentration of the active metabolite of losartan, potentially diminishing its therapeutic effect. Consumption of grapefruit juice should be avoided during losartan tablet therapy.

Special precautions for use.

Hypersensitivity

Angioedema. Patients with a history of angioedema (facial, lip, throat, and/or tongue swelling) should be closely monitored.

Intestinal angioedema. Cases of intestinal angioedema have been reported in patients receiving treatment with angiotensin II receptor antagonists, including losartan (see section "Adverse reactions"). Patients presented with abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, this medicinal product should be discontinued and appropriate monitoring initiated until complete symptom resolution.

Arterial hypotension and fluid-electrolyte imbalance

Symptomatic arterial hypotension, particularly after administration of the first dose or dose escalation, may occur in patients with reduced intravascular volume or sodium depletion caused by potent diuretics, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected prior to initiating losartan therapy or a lower starting dose should be used. These recommendations also apply to children aged 6 years and older.

Electrolyte imbalance

Electrolyte imbalance is frequently observed in patients with renal impairment (with or without diabetes), which should be taken into account. In patients with type 2 diabetes and nephropathy, the incidence of hyperkalemia was higher with losartan treatment compared to placebo. Therefore, plasma potassium concentration and creatinine clearance should be monitored frequently, especially in patients with heart failure and creatinine clearance of 30–50 mL/min.

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

Hepatic impairment

Since pharmacokinetic data indicate a substantial increase in plasma losartan concentrations in patients with liver cirrhosis, dose reduction should be considered in patients with a history of hepatic impairment. There is no experience with therapeutic use of losartan in patients with severe hepatic impairment; therefore, losartan should not be administered to such patients.

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

Renal impairment

Changes in renal function, including renal failure, have been reported and were 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 cause increases in blood urea nitrogen and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary 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 solitary kidney.

Use in children with renal impairment

Losartan is not recommended for use in children with GFR <30 mL/min/1.73 m² due to lack of relevant data for such use.

Renal function should be monitored regularly during losartan treatment, as deterioration is possible. 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 worsens renal function; therefore, this combination is not recommended.

Kidney transplantation

There are no data on the safety of using the medicinal product in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Antihypertensive agents acting via inhibition of the renin-angiotensin system are generally ineffective in patients with primary hyperaldosteronism. Therefore, losartan is not recommended for this patient group.

Coronary artery disease and cerebrovascular disorders

As with other antihypertensive agents, 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 agents affecting the RAAS, in patients with heart failure, with or without renal impairment, there is a risk of developing severe arterial hypotension and renal dysfunction (often acute).

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

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Dual blockade of the RAAS

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended.

In cases where dual blockade is considered absolutely necessary, it should be performed only under specialist supervision with careful monitoring of renal function, fluid-electrolyte balance, and blood pressure. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Pregnancy

Losartan should not be used during pregnancy or in women planning to become pregnant. Unless therapy with losartan is considered essential, patients planning pregnancy should be switched to an alternative antihypertensive treatment with an established safety profile during pregnancy. If pregnancy is diagnosed, losartan therapy should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Other warnings

Losartan and other angiotensin antagonists are less effective in reducing blood pressure in black patients compared to other patients, possibly due to lower renin activity in black patients with arterial hypertension.

Losartan-Teva contains lactose. This medicinal product should not be administered to patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Use during pregnancy and in women planning to become pregnant is contraindicated.

Patients planning pregnancy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy. Upon confirmation of pregnancy, losartan therapy should be discontinued immediately and, if needed, alternative therapy initiated.

It has been established that use of angiotensin II receptor antagonists during the second and third trimesters of pregnancy induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) in humans.

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

Infants whose mothers received losartan during pregnancy should be closely observed for signs of arterial hypotension.

Breastfeeding

Losartan should not be used during breastfeeding. During lactation, alternative medicinal products with a better-established safety profile for use during breastfeeding should be prescribed.

Ability to influence the speed of reaction when driving or operating machinery.

No studies have been conducted on the effect of the medicinal product on the ability to drive or operate machinery. However, the possibility of adverse reactions such as dizziness and somnolence, especially at the beginning of treatment and during dose escalation, should be considered.

Dosage and Administration

Losartan tablets should be taken with a glass of water. The drug can be administered independently of food intake.

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 treatment. For some patients, increasing the dose to 100 mg once daily (in the morning) may be beneficial.

Losartan can be used in combination with other antihypertensive agents, particularly diuretics (e.g., hydrochlorothiazide).

Patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥0.5 g per day

The recommended 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 therapy. Losartan may be used concomitantly with other antihypertensive agents (e.g., diuretics, calcium channel blockers, α- or β-blockers, centrally acting agents), as well as with insulin and other hypoglycemic agents (e.g., sulfonylureas, glitazones, and glucosidase inhibitors).

Heart failure

For patients with chronic heart failure, the recommended initial dose of losartan is 12.5 mg once daily. The dose is usually titrated at weekly intervals (12.5 mg once daily, 25 mg once daily, 50 mg once daily, up to a maximum of 100 mg once daily) depending on individual tolerability. In some cases, the dose may be further increased to a maximum of 150 mg once daily.

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

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

Special patient groups

Use in patients with reduced circulating blood volume

In patients with reduced circulating blood volume (e.g., due to treatment with high-dose diuretics), therapy should be initiated at a dose of 25 mg of losartan 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

A lower starting dose should be considered for patients with a history of hepatic impairment. There is no experience in treating patients with severe hepatic impairment; therefore, losartan is contraindicated in such patients.

Pediatric use (aged 6 to 18 years)

For children who can swallow tablets and whose body weight is between 20 kg and 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. Dose adjustments should be based on the effect on arterial blood pressure.

For patients with body weight above 50 kg, the recommended 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 safety and efficacy in this patient group.

The drug is not recommended for pediatric patients with eGFR <30 mL/min/1.73 m² due to lack of relevant data.

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

Use in elderly patients

Dose adjustment is generally not required in elderly patients. However, losartan may be initiated at a dose of 25 mg once daily in patients over 75 years of age.

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. Depending on the degree of intoxication, symptoms such as arterial hypotension, tachycardia, or bradycardia (which may result from parasympathetic [vagal] stimulation) may occur.

Treatment. Management depends on the time elapsed since drug ingestion, as well as the nature and severity of symptoms. In case of symptomatic hypotension, supportive therapy should be initiated. The primary goal is stabilization of cardiovascular function. After oral overdose, administration of activated charcoal in an appropriate dose is indicated. Subsequently, vital signs should be monitored and corrected as necessary. Neither losartan nor its active metabolite is significantly removed by hemodialysis.

Adverse reactions

The most common adverse event observed during losartan administration was dizziness.

Adverse reactions are categorized by frequency as follows: 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).

Table 1.

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

Adverse reaction	Frequency of adverse reactions in different 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
Blood and lymphatic system disorders
anemia			common		frequency unknown
thrombocytopenia					frequency unknown
Immune system disorders
hypersensitivity reactions, anaphylactic reactions, angioedema* and vasculitis**					rare
Psychiatric disorders
depression					frequency unknown
Nervous system disorders
dizziness	common	common	common	common
drowsiness	uncommon
headache	uncommon		uncommon
sleep disturbance	uncommon
paraesthesia			rare
migraine					frequency unknown
dysgeusia					frequency unknown
Ear and labyrinth disorders
vertigo	common	common
tinnitus					frequency unknown
Cardiac disorders
palpitations	uncommon
angina pectoris	uncommon
syncope			rare
atrial fibrillation			rare
acute cerebrovascular accident			rare
Vascular disorders
(orthostatic) hypotension (including dose-dependent orthostatic effects)II	uncommon		common	common
Respiratory, thoracic and mediastinal disorders
dyspnea			uncommon
cough			uncommon		frequency unknown
Gastrointestinal disorders
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
Skin and subcutaneous tissue disorders
urticaria			uncommon		frequency unknown
pruritus			uncommon		frequency unknown
rash	uncommon		uncommon		frequency unknown
photosensitivity					frequency unknown
Musculoskeletal and connective tissue disorders
myalgia					frequency unknown
arthralgia					frequency unknown
rhabdomyolysis					frequency unknown
Renal and urinary disorders
renal function impairment			common
renal failure			common
Reproductive system disorders
erectile dysfunction/impotence					frequency unknown
General disorders
asthenia	uncommon	common	uncommon	common
fatigue	uncommon	common	uncommon	common
edema	uncommon
malaise					frequency unknown
Investigations
hyperkalemia	common		uncommon†	common‡
increased alanine aminotransferase (ALT) levels§	rare
increased blood urea nitrogen, serum creatinine and serum potassium levels			common
hyponatremia					frequency unknown
hypoglycemia				common

*Including angioedema of the larynx, glottis, face, lips, pharynx, and/or tongue (which may cause airway obstruction); in some of these patients, there have been reports of a history of angioedema related to the use of other medicinal products, including ACE inhibitors.

**Including Henoch–Schönlein purpura.

II Particularly in patients with reduced blood volume, such as those with severe heart failure or those receiving high doses of diuretics.

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

‡In a clinical study 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.

§Usually resolves after discontinuation of treatment.

Additional adverse reactions occurring more frequently in patients treated with losartan than in those receiving placebo (frequency unknown): back pain, urinary tract infections, and influenza-like symptoms.

Renal and urinary disorders. As a result of RAAS inhibition, changes in renal function, including renal failure, have been observed in patients at increased risk. These changes may be reversible and resolve upon discontinuation of therapy.

Pediatric population. The adverse reaction profile in children and adolescents is similar to that in adults. Data on the use of the drug in children are limited.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

12.5 mg tablets: 10 tablets in a blister; 3 blisters in a cardboard box.

25 mg tablets: 10 tablets in a blister; 3 blisters in a cardboard box, or 15 tablets in a blister; 2 blisters in a cardboard box.

50 mg tablets: 10 tablets in a blister; 3 or 9 blisters in a cardboard box, or 15 tablets in a blister; 2 or 6 blisters in a cardboard box.

100 mg tablets: 10 tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturers. JSC "Teva Pharmaceutical Plant".

Teva Pharma S.L.U.

Manufacturers' locations and addresses of sites of operation.

Site 1; Palagyi St. 13, H-4042 Debrecen, Hungary.

Poligono Industrial Malpica c/C No. 4, 50016, Zaragoza, Spain.