Presartan®-50
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PERSARTAN®-50 (PRESARTAN®-50)
Composition:
Active ingredient: losartan potassium;
One tablet contains losartan potassium 50 mg;
Excipients: maize starch, microcrystalline cellulose, talc, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate;
Coating: talc, hypromellose, titanium dioxide (E 171), propylene glycol 6000.
Medicinal form. Film-coated tablets.
Main physico-chemical properties: oval, biconvex, film-coated tablets, white to almost white in color, with "50" embossed on one side and "BL" on the other.
Pharmacotherapeutic group. Simple angiotensin II antagonists.
ATC code C09CA01.
Pharmacological Properties
Pharmacodynamics
Losartan is a synthetic angiotensin II receptor antagonist (AT1-type) for oral administration. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and one of the most important factors 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 a range of important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation.
Losartan selectively binds to the AT1 receptor. In both in vitro and in vivo conditions, losartan and its pharmacologically active metabolite—carboxylic acid (E-3174)—block all physiologically significant effects of angiotensin II, regardless of its source or pathway of synthesis.
Losartan selectively binds to the AT1 receptor, with no binding to or blockade of other hormone receptors or ion channels. Additionally, losartan does not inhibit ACE (kininase II), the enzyme responsible for bradykinin degradation. As a result, effects not directly related to AT1 receptor blockade, such as those mediated by increased bradykinin activity, are not associated with losartan use.
During losartan therapy, the removal of angiotensin II's negative feedback on renin secretion increases plasma renin activity. This increase leads to elevated plasma angiotensin II levels. Despite this, 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 exhibit higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more potent than losartan.
Losartan reduces overall cardiovascular mortality, stroke, and myocardial infarction in patients with arterial hypertension and left ventricular hypertrophy, and provides renal protection in patients with type 2 diabetes and proteinuria.
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 within 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 its active metabolite following intravenous administration or oral intake. After intravenous or oral administration of radiolabeled 14C-losartan potassium, circulating plasma radioactivity is generally associated with the presence of losartan and its metabolites. Minimal conversion of losartan to its active metabolite was observed 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. Following oral administration, about 4% of the dose is excreted unchanged in urine, and approximately 6% is excreted in urine 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. After oral administration of 14C-labeled losartan, approximately 35% of radioactivity is recovered in urine and 58% in feces.
Pharmacokinetics in Specific Patient Populations
Elderly Patients
Plasma concentrations of losartan and its active metabolite in elderly hypertensive patients do not significantly differ from those in younger hypertensive patients.
Sex
Plasma concentrations of losartan were twice as high in women with arterial hypertension compared to men. Plasma concentrations of the active metabolite did not differ between men and women.
Hepatic and Renal Impairment
Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of losartan and its active metabolite were 1.7 and 5 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. Compared to the area under the concentration-time curve (AUC) in patients with normal renal function, the AUC of losartan in patients undergoing hemodialysis was approximately twice as high. Plasma concentrations of the active metabolite remain unchanged in patients with renal impairment and 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. Results indicate similar pharmacokinetic parameters of losartan after oral administration in neonates and children up to 2 years of age, preschool children, school-aged children, and adolescents. Pharmacokinetic parameters of the metabolite showed greater variability depending on age group. 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.
For the treatment of essential hypertension in adults, as well as in children and adolescents aged 6 to 18 years.
For the treatment of kidney disease in adult patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day — as part of antihypertensive therapy.
For the treatment of chronic heart failure (in patients aged 60 years and older) when angiotensin-converting enzyme (ACE) inhibitors are considered unsuitable due to intolerance, particularly cough, or are contraindicated. Patients with heart failure whose condition has been stabilized on ACE inhibitor therapy should not be switched to losartan. The patient must have a left ventricular ejection fraction ≤ 40%, clinically stable condition, and be on established therapy for chronic heart failure.
For 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.
‒ Severe hepatic impairment.
‒ Pregnancy, planned pregnancy (see section "Use in pregnancy or breast-feeding").
‒ Pediatric age under 6 years.
‒ Concomitant use of medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 ml/min/1.73 m²).
Interaction with other medicinal products and other types of interactions.
Other antihypertensive agents may enhance the hypotensive effect of losartan. Concomitant use with other drugs that may cause hypotension as an adverse reaction (e.g., tricyclic antidepressants, antipsychotics, baclofen, and amifostine) increases the risk of arterial hypotension.
Losartan is primarily metabolized by the cytochrome P450 (CYP) 2C9 system to its active carboxylic acid metabolite. It has been established that fluconazole (a CYP2C9 inhibitor) reduces exposure to the active metabolite by approximately 50%. Concomitant treatment with losartan and rifampicin (an enzyme inducer) results in a 40% reduction in plasma concentration of the active metabolite. 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).
Concomitant use of potassium-sparing agents (e.g., potassium-sparing diuretics such as spironolactone, triamterene, amiloride) or agents that may increase potassium levels (e.g., heparin), potassium-containing supplements, or potassium-containing salt substitutes may lead to increased serum potassium levels. Concomitant use of such agents is not recommended.
Reversible increases in serum lithium concentrations, as well as lithium toxicity, have been reported with concomitant use of lithium and ACE inhibitors. Such cases have also been very rarely reported with angiotensin II receptor antagonists.
Concomitant use of lithium and losartan should be performed with caution. If such combination therapy is considered necessary, monitoring of serum lithium concentrations during combination therapy is recommended.
When angiotensin II antagonists are used concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, nonselective NSAIDs), the antihypertensive effect may be attenuated. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs may lead to deterioration of renal function, including possible development of acute renal failure, and to increased serum potassium levels, particularly in patients with pre-existing renal impairment. Such combinations should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated, and monitoring of renal function at the start of concomitant therapy and periodically thereafter may be advisable.
With dual blockade of the renin-angiotensin-aldosterone system (e.g., adding an ACE inhibitor to angiotensin II receptor antagonist therapy), careful monitoring of renal function is required, and concomitant medication may need to be limited. Some studies have shown that in patients with atherosclerosis, heart failure, or diabetic neuropathy, dual blockade of the renin-angiotensin-aldosterone system leads to a higher incidence of adverse events such as hypotension, compared to treatment with a single agent acting on the renin-angiotensin-aldosterone system.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Clinical trials indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of adverse reactions such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to use of a single agent from these classes (see sections "Contraindications", "Special precautions for use").
Grapefruit juice contains components that inhibit CYP450 enzymes and may reduce the concentration of the active metabolite of losartan, thereby diminishing its therapeutic effect. Grapefruit juice should be avoided during losartan tablet administration.
Special precautions for use.
Hypersensitivity
Angioedema. Patients with a history of angioedema (facial, lip, throat, and/or tongue swelling) should be monitored frequently.
Intestinal angioedema
Cases of intestinal angioedema have been reported in patients treated with angiotensin II receptor antagonists, [including
Arterial hypotension and fluid-electrolyte imbalance
Symptomatic arterial hypotension, particularly after the first dose or dose escalation, may occur in patients with reduced intravascular volume or sodium depletion caused by potent diuretics, salt-restricted diet, diarrhea, or vomiting. Such conditions should be corrected prior to initiating losartan therapy or a lower starting dose should be considered (see "Dosage and administration"). These recommendations also apply to children aged 6 to 18 years.
Electrolyte imbalance
Electrolyte imbalances are frequently observed in patients with impaired renal function (with or without diabetes mellitus) and should be taken into account. In patients with type 2 diabetes mellitus and nephropathy, the incidence of hyperkalemia was higher during treatment with losartan. Therefore, plasma potassium concentrations and creatinine clearance should be monitored frequently, 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 drugs that may increase serum potassium levels (e.g., products containing trimethoprim) with losartan is not recommended (see section "Special precautions for use").
Hepatic impairment
Based on pharmacokinetic data indicating a marked 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 therapeutic experience with the use of the drug in patients with severe hepatic impairment. Therefore, losartan should not be administered to patients with severe hepatic impairment.
Losartan is not recommended for use in children with hepatic impairment.
Renal impairment
Changes in renal function, including renal failure, have been reported and are associated with inhibition of the renin-angiotensin system (particularly in patients whose renal function depends on the renin-angiotensin-aldosterone system, i.e., patients with severe heart failure or pre-existing renal impairment).
Drugs affecting the renin-angiotensin-aldosterone system may increase blood urea and serum creatinine levels 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. The medicinal product is not recommended for use in children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of appropriate use data.
Renal function should be monitored regularly during losartan treatment, as deterioration may occur. This is particularly relevant in situations where losartan is used in the presence of other pathological 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 is no experience regarding the safety of the drug in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to drugs acting via inhibition of the renin-angiotensin system. 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
When drugs affecting the renin-angiotensin-aldosterone system are used in patients with heart failure, with or without renal impairment, there is a risk of developing severe arterial hypotension and (often acute) renal dysfunction. There is insufficient therapeutic experience with losartan 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 patients. Caution is also required when losartan is used concomitantly with β-blockers.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
The medicinal product should be prescribed with particular caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Data indicate that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren for dual RAAS blockade is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
When combination therapy (dual blockade) is considered absolutely necessary, treatment should be administered only under physician supervision with frequent and careful monitoring of renal function, fluid-electrolyte balance, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Other warnings
As established for ACE inhibitors, losartan and other angiotensin antagonists are less effective in patients of black race than in other patients, possibly due to low renin activity in black patients with arterial hypertension.
This medicinal product contains sodium starch glycolate (type A). It should be used with caution in patients on a sodium-restricted diet.
The medicinal product also contains propylene glycol, which may cause symptoms similar to those associated with alcohol consumption.
Use during pregnancy or breastfeeding
Pregnancy. The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this product, therapy should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.
Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Since there are no epidemiological data on the risk associated with angiotensin II receptor antagonists (ARBs), such a risk may exist with this class of drugs. It is known that ARB use during the second and third trimesters induces fetotoxicity (renal dysfunction, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If ARBs are used during the second trimester of pregnancy, ultrasound examination is recommended to assess renal function and skull ossification.
Newborns whose mothers were treated with ARBs should be monitored frequently for the development of arterial hypotension.
Breastfeeding. The use of losartan during breastfeeding is contraindicated. Alternative treatment with medicinal products having a better-established safety profile is recommended.
Ability to influence reaction speed when driving or operating machinery
There are no data 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 should be considered, particularly at the beginning of treatment and during dose escalation.
Method of Administration and Dosage
The medicinal product can be taken regardless of food intake, swallowed with 1 glass of water.
Arterial Hypertension
The usual initial and maintenance dose for most patients is 50 mg of the drug once daily. The 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.
The medicinal product can be used in combination with other antihypertensive agents, particularly diuretics (e.g., hydrochlorothiazide).
Patients with Arterial Hypertension and Type 2 Diabetes Mellitus (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-receptor blockers, centrally acting agents), as well as with insulin and other widely used hypoglycemic agents (e.g., sulfonylureas, glitazones, and glucosidase inhibitors).
Heart Failure
The usual initial dose of losartan in patients with chronic heart failure is 12.5 mg once daily (losartan should be administered in the appropriate dosage form). The dose is typically titrated at weekly intervals (i.e., 12.5 mg daily, 25 mg daily, 50 mg daily) up to the usual maintenance dose of 50 mg once daily, depending on individual tolerability.
Reduction of Stroke Risk in Patients with Arterial Hypertension and Left Ventricular Hypertrophy Confirmed by ECG
The usual initial dose is 50 mg of the drug once daily. Depending on blood pressure changes prior to treatment, a low dose of hydrochlorothiazide should be added and/or the losartan dose increased to 100 mg once daily.
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 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 with losartan in patients with severe hepatic impairment; therefore, losartan is contraindicated in this patient group.
Use in Children. 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—losartan should be administered in the appropriate dosage form. 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 blood pressure.
For 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.
Use in Elderly Patients. Generally, no adjustment of the initial dose is required for elderly patients, although initiating treatment at a dose of 25 mg may be considered for patients over 75 years of age.
Children.
Safety and efficacy of the medicinal product in children under 6 years of age have not been established.
The medicinal product is not recommended for children with glomerular filtration rate < 30 mL/min/1.73 m² due to lack of relevant data.
Losartan is also not recommended for use in children with hepatic impairment.
Overdose.
Symptoms of Intoxication. Cases of overdose have not been reported. Depending on the extent of overdose, arterial hypotension, tachycardia, or bradycardia may occur. Bradycardia may result from parasympathetic (vagal) stimulation.
Treatment of Intoxication depends on the time elapsed since drug ingestion and the nature and severity of symptoms.
Cardiovascular function should be stabilized first. After oral intake of the medicinal product, activated charcoal in an appropriate dose is indicated. Subsequently, vital signs should be monitored frequently and corrected as necessary. Losartan and its active metabolites are not removed by hemodialysis.
Adverse reactions.
The most common adverse reaction is dizziness.
Nervous system disorders: dizziness, vertigo, somnolence, headache, insomnia, muscle cramps, paresthesia, migraine, dysgeusia.
Cardiac disorders: palpitations, dose-dependent orthostatic effect, tachycardia, angina pectoris, syncope, atrial fibrillation, stroke.
Vascular disorders: symptomatic hypotension, especially in patients with intravascular volume depletion (e.g., in severe heart failure or patients treated with high-dose diuretics), arterial hypotension including orthostatic hypotension, tachycardia.
Gastrointestinal disorders: abdominal pain, dyspepsia, constipation, diarrhea, nausea, vomiting, pancreatitis, hepatitis, hepatic function abnormalities. Angioneurotic edema of the intestine – rare.
Respiratory, thoracic and mediastinal disorders: cough, rhinitis, sinusitis, pharyngitis, upper respiratory tract infection, dyspnea.
General disorders and administration site conditions: asthenia, weakness, edema, influenza-like symptoms, malaise.
Ear and labyrinth disorders: vertigo, tinnitus.
Skin and subcutaneous tissue disorders: urticaria, pruritus, rash, photosensitivity, erythroderma.
Blood and lymphatic system disorders: anemia, thrombocytopenia.
Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, rhabdomyolysis, muscle cramps.
Renal and urinary disorders: urinary tract infections; as a consequence of renin-angiotensin-aldosterone system inhibition — changes in renal function, including renal failure in patients at risk (may be reversible upon discontinuation of therapy).
Immune system disorders: hypersensitivity reactions (anaphylactic reactions, angioedema, including laryngeal and glottis edema leading to airway obstruction, and/or facial, lip, throat, and/or tongue swelling) — in some patients history of angioedema associated with other drugs, including ACE inhibitors; vasculitis, including Henoch-Schönlein purpura.
Reproductive system and breast disorders: erectile dysfunction/impotence.
Psychiatric disorders: depression.
Laboratory findings: increased levels of ALT (alanine aminotransferase), hyperkalemia (frequent in patients receiving 150 mg dose instead of 50 mg; in patients with type II diabetes), hypoglycemia, hyponatremia, increased blood urea nitrogen, serum creatinine.
Changes in standard laboratory parameters were rarely associated with the use of losartan tablets. Alanine aminotransferase (ALT) levels were rarely elevated and usually returned to normal after discontinuation of the drug. Hyperkalemia (serum potassium level > 5.5 mmol/L) was observed in 1.5% of patients with arterial hypertension.
Children.
The adverse reaction profile in children is similar to that in adult patients. Data on adverse reactions in children are limited.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.
Packaging.
10 tablets in a blister; 3 blisters in a cardboard box.
14 tablets in a blister; 2 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Ipsa Laboratories Limited.
Manufacturer's address and place of business.
Plot No. 255/1, Village – Atal, U.T. Dadra and Nagar Haveli, 396 230 Silvassa, India.