Pharmacological properties
Pharmacodynamics. Losartan potassium is an angiotensin II (type AT 1) receptor antagonist. Angiotensin II, formed from angiotensin I in a reaction involving APF (kininase II), is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component of the pathophysiological mechanisms of AGF. Angiotensin II also binds to the AT 1 receptor, which is found in many tissues (vascular smooth muscle, adrenal glands, kidneys and heart), determining a number of important biological effects, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates the proliferation of smooth muscle cells.
Losartan and its active carboxylic acid metabolite block all physiologically significant effects of angiotensin II, regardless of the source or route of synthesis.
Losartan selectively binds to the AT1 receptor and does not bind to or block other hormone receptors or ion channels.
Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that catalyzes the degradation of bradykinin. Consequently, effects not directly related to AT1 receptor blockade, such as increased bradykinin-mediated effects, are not associated with the use of losartan.
When losartan is used, the elimination of the negative feedback loop of angiotensin II on renin secretion leads to an increase in plasma renin activity. This increase in activity leads to an increase in plasma angiotensin II levels. Despite this increase, antihypertensive activity and suppression of plasma aldosterone concentrations are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and angiotensin II levels return to baseline within 3 days.
Both losartan and its main metabolite have a higher affinity for AT1 receptors than AT2. The active metabolite is 10-40 times more active than losartan.
Pharmacokinetics. After oral administration, losartan is well absorbed and undergoes first-pass metabolism. Systemic bioavailability is about 33%. Almost 14% of an oral dose of losartan is converted to the active carboxyl metabolite. C max of losartan and its active metabolite is achieved after 1 and 3-4 hours, respectively. Losartan and the active metabolite are extensively bound to plasma proteins, mainly albumin. T ½ of losartan is 2 hours, of the active metabolite - 6-9 hours. The pharmacokinetics of losartan and the active metabolite are linear for oral doses of losartan up to 200 mg and do not change with time. Losartan and the active metabolite accumulate in plasma in the event of repeated once-daily dosing. About 4% of the dose is excreted unchanged in the urine and about 6% - in the form of the active metabolite. Biliary excretion of the drug accounts for a certain part of the elimination of losartan and its active metabolite - about 35% of the dose is excreted in the urine and almost 58% in the feces.
Elderly patients. No significant changes in pharmacokinetic characteristics were observed in elderly patients with hypertension compared to young patients.
Gender. Plasma concentrations of losartan in women with hypertension were 2 times higher than those in men. No gender-dependent dependence of the concentration of the active metabolite was found.
Hepatic and renal impairment: Plasma concentrations of losartan and its active metabolite in patients with hepatic impairment are 1.7-5 times higher than those in patients with normal hepatic function.
Plasma concentrations of losartan in patients with creatinine clearance of 10 ml/min did not differ from those in healthy subjects. The AUC in patients with severe renal impairment was 2 times higher than the AUC of losartan in patients with normal renal function. Plasma concentrations of the active metabolite of losartan remained unchanged. Losartan and its active metabolite cannot be removed by hemodialysis.
Pharmacokinetics in children. The active metabolite of losartan is formed in patients of all age groups. The pharmacokinetics of losartan after oral administration are similar in neonates and children aged 2 years and older, preschool children, school-age children and adolescents. The pharmacokinetics of the metabolite are more age-dependent, especially when comparing preschool children and adolescents. Exposure in neonates and children aged less than 2 years is relatively high.
Indication
Treatment of essential hypertension in adults and children aged 6 years and over. Treatment of kidney disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria ≥0.5 g/day - as part of a combination therapy. Treatment of chronic heart failure (in patients over 60 years of age) in cases where the use of ACE inhibitors is considered impossible due to intolerance (especially with cough) or in the presence of contraindications. For patients with heart failure whose condition is stable while taking ACE inhibitors, the appointment of the drug CLOSART is not advisable. The patient's left ventricular ejection fraction should be ≤40%, the condition should be clinically stable, and the patient should also adhere to the established treatment regimen for chronic heart failure. Reduction of the risk of stroke in adult patients with hypertension and left ventricular hypertrophy, confirmed by ECG.
Application
Take the tablets regardless of meals, with 1 glass of water.
Hypertension. For most patients, the initial and maintenance dose of Closart is 50 mg once daily. The maximum antihypertensive effect is achieved 3-6 weeks after the start of treatment. For some patients, an increase in the dose to 100 mg once daily (in the morning) may be beneficial.
Closart can be used in combination with other antihypertensive drugs, especially with diuretics (e.g. hydrochlorothiazide).
Patients with hypertension, type 2 diabetes mellitus and proteinuria (≥0.5 g/day). Usually the initial dose of Closart is 50 mg once a day. It can be increased to 100 mg once a day depending on the blood pressure readings 1 month after the start of treatment. Closart can be used together with other antihypertensive agents (diuretics, calcium channel blockers, α- or β-receptor blockers, centrally acting drugs), as well as with insulin and other hypoglycemic agents (e.g. sulfonylureas, glitazones and glucosidase inhibitors).
Heart failure. The usual starting dose of losartan in patients with chronic heart failure is 12.5 mg once daily. The dose is usually titrated at weekly intervals (i.e. 12.5; 25; 50 mg/day) to the usual maintenance dose of 50 mg (1 tablet of Closartan 50 mg) once daily, depending on individual tolerability.
Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy, documented by ECG. The usual starting dose is 50 mg once daily. Depending on changes in blood pressure, it may be necessary to prescribe a lower dose of hydrochlorothiazide and/or increase the dose of losartan to 100 mg once daily.
Certain patient groups
Use in patients with reduced BCC. In patients with reduced circulating blood volume (for example, due to the use of high doses of diuretics), therapy should be initiated with a dose of 25 mg once daily.
Use in patients with renal insufficiency and patients undergoing hemodialysis. When prescribing Closart to patients with impaired renal function, as well as patients undergoing hemodialysis, no initial dose adjustment is required.
Use in patients with a history of hepatic impairment. For patients with a history of hepatic impairment, a lower dose should be considered. There is no experience in patients with severe hepatic impairment, therefore Closart is contraindicated in this group of patients.
Use in children over 6 years of age. For children who can swallow tablets and weigh between 20 kg and 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 according to changes in blood pressure.
In patients weighing 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 100 mg) per day have not been studied in children.
Closart is not recommended for use in children with impaired liver function.
Closart is also not recommended for use in children with a glomerular filtration rate (GFR) of 30 ml/min/1.73 m2, as there are no relevant data on its use.
Use in patients over 75 years of age. Therapy should be initiated at a dose of 25 mg once daily. Dose adjustment is usually not required.
Contraindication
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe hepatic impairment. Pregnant women or women planning to become pregnant (see Use during pregnancy and breastfeeding). Concomitant use of losartan and aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) is contraindicated (see Use, Special warnings and precautions for use, Interactions).
Side effects
From the nervous system: dizziness, drowsiness, headache, insomnia, muscle cramps, paresthesia, stroke, migraine, dysgeusia.
From the side of the organs of hearing and labyrinth: vertigo, tinnitus.
Psychiatric: depression.
Cardiac: palpitations, syncope, angina pectoris, tachycardia, atrial fibrillation.
Vascular system: symptomatic hypotension (especially in patients with intravascular dehydration, e.g. patients with severe heart failure or during treatment with high doses of diuretics), dose-dependent orthostatic effect.
On the part of the digestive system: abdominal pain, dyspepsia, constipation, diarrhea, pancreatitis, nausea, vomiting.
From the hepatobiliary system: hepatitis, liver dysfunction.
Respiratory system: cough, shortness of breath, rhinorrhea, sinusitis, pharyngitis, upper respiratory tract infection.
Renal and urinary tract disorders: changes in renal function, including renal failure in patients at risk (such changes in renal function may be reversible upon discontinuation of therapy), urinary tract infections.
From the blood and lymphatic system: anemia, thrombocytopenia.
General condition and disorders related to the method of administration of the drug: asthenia/weakness, malaise, edema, flu-like symptoms.
Musculoskeletal and connective tissue disorders: back pain, muscle pain, joint pain, rhabdomyolysis.
Reproductive system and breast disorders: erectile dysfunction/impotence.
Immune system disorders: hypersensitivity reactions (anaphylactic reactions, angioedema, including laryngeal and glottis swelling leading to airway obstruction and/or swelling of the face, lips, pharynx and/or tongue); some patients have had a history of angioedema associated with the use of other drugs, including ACE inhibitors; vasculitis, including Henoch-Schönlein purpura.
Laboratory indicators: hypoglycemia, hyperkalemia, hyponatremia, increased ALT levels, increased blood urea levels, and blood plasma creatinine levels.
Special instructions
Pregnancy. The use of angiotensin II receptor antagonists is contraindicated during pregnancy. Patients receiving angiotensin II receptor antagonists and planning pregnancy should be changed to antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see Contraindications and Use in Pregnancy and Lactation).
Hypersensitivity. Angioedema. While taking the drug, patients with a history of edema (swelling of the face, lips, throat and / or tongue) should constantly monitor their general condition.
Hypotension and fluid and electrolyte imbalance. Symptomatic hypotension, especially after the first dose or its increase, may occur in patients with reduced circulating blood volume or sodium deficiency caused by the use of strong diuretics, dietary salt restriction, diarrhea or vomiting. Such conditions require correction before starting treatment with losartan or a reduction in the initial dose of the drug. The same recommendations apply to children over 6 years of age.
Electrolyte imbalance: Electrolyte imbalance is frequently observed in patients with renal impairment (with or without diabetes mellitus) and should be considered. Plasma potassium concentration (possibility of hyperkalemia) and creatinine clearance should also be closely monitored, especially in patients with heart failure and creatinine clearance of 30-50 ml/min.
The concomitant use of losartan and potassium-sparing diuretics, potassium supplements, and salt substitutes containing potassium is not recommended.
Hepatic impairment: Given the pharmacokinetic data indicating a significant increase in plasma concentrations of losartan in patients with cirrhosis, a dose reduction should be considered in patients with a history of hepatic impairment. There is no experience in patients with severe hepatic impairment.
The drug is not recommended for use in children with liver dysfunction.
Renal impairment: Changes in renal function, including renal failure, have been reported, which have been associated with suppression of the renin-angiotensin system (particularly in patients with renal function dependent on the renin-angiotensin-aldosterone system (RAAS), i.e. patients with severe cardiac dysfunction or pre-existing renal dysfunction).
Drugs that affect the RAAS may cause increases in blood urea and creatinine levels in patients with bilateral renal artery stenosis, renal artery stenosis, or stenosis of the artery to a solitary kidney.
These changes in renal function may be reversible upon discontinuation of therapy. Clozaril 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 drug is not recommended for use in children with a GFR of 30 ml/min/1.73 m2, as there are no relevant data on use.
During the period of use of Closart, kidney function should be regularly checked, as its deterioration is possible. This is especially true when Closart is used in the presence of other pathological conditions (fever, dehydration) that may affect kidney function.
The simultaneous use of Closart and ACE inhibitors worsens kidney function, so this combination is not recommended.
Kidney transplantation: There is no experience regarding the safety of losartan in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism: Patients with primary hyperaldosteronism usually do not respond to drugs that act by inhibiting the renin-angiotensin system. Therefore, Clozaril is not recommended for this group of patients.
Coronary artery disease and cerebrovascular disease: As with other antihypertensive drugs, excessive blood pressure reduction in patients with ischemic coronary artery disease and cerebrovascular disease may lead to myocardial infarction or stroke.
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 patient groups. Caution should be exercised when losartan and β-blockers are used concomitantly.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, Closart should be administered with extreme caution to patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Caution: As has been shown for ACE inhibitors, losartan and other angiotensin antagonists are less effective in black patients than in non-black patients, possibly because of lower renin activity in black hypertensive patients.
Dual blockade of the RAAS. Hypertension, syncope, stroke, hyperkalemia, and renal changes (including acute renal failure) have been reported in susceptible individuals, especially when drugs that affect this system are combined (see Interactions with other drugs). Therefore, dual blockade of the RAAS by combining angiotensin II receptor blockers (ARBs) with ACE inhibitors or aliskiren is not recommended.
The combination with aliskiren is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR 60 ml/min/1.73 m2).
Use during pregnancy and breastfeeding
Pregnancy. The drug is contraindicated for use in pregnant women or women planning to become pregnant (see Side Effects and Precautions). If pregnancy is confirmed during treatment, the drug should be discontinued immediately and replaced with another drug approved for use in pregnant women.
It is known that the use of angiotensin II receptor antagonists in the II and III trimesters induces fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If angiotensin II receptor antagonists were used in the second trimester of pregnancy, an ultrasound scan is recommended to check kidney function and the condition of the skull bones.
Newborns whose mothers have taken angiotensin II receptor antagonists should be frequently observed for the development of hypotension.
Breastfeeding: As no information is available regarding the use of losartan during breast-feeding, this drug is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Children: The safety and efficacy of Closart in children under 6 years of age have not been established.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Data on the effect of losartan on the ability to drive vehicles or work with other mechanisms are limited. The possibility of developing side effects such as dizziness and drowsiness should be taken into account, especially at the beginning of treatment and when increasing the dose of the drug.
Interactions
Other antihypertensive agents may enhance the hypotensive effect of losartan. Concomitant use with other drugs that can induce such a side effect as arterial hypotension (tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of arterial hypotension.
Losartan is primarily metabolized by cytochrome P450 (CYP) 2C9 to the active metabolite, carboxylic acid. Fluconazole has been shown to reduce exposure to the active metabolite by approximately 50%, and concomitant treatment with losartan and rifampicin (an inducer of metabolic enzymes) has been shown to reduce plasma concentrations of the active metabolite by 40%. The clinical significance of this effect is unknown. There are differences in exposure when losartan is coadministered with fluvastatin (a weak CYP 2C9 inhibitor).
As with other drugs that block angiotensin II or its effects, concomitant use of drugs that retain potassium in the body (e.g. potassium-sparing diuretics: spironolactone, triamterene, amiloride) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium may lead to increases in plasma potassium. Concomitant use of such drugs is not recommended.
With the simultaneous use of angiotensin II antagonists and non-steroidal anti-inflammatory drugs (e.g. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses, non-selective NSAIDs), the antihypertensive effect may be weakened. The simultaneous use of angiotensin II antagonists or diuretics with NSAIDs may lead to an increased risk of worsening of renal function, including the possible development of acute renal failure, as well as an increase in plasma potassium levels, especially in patients with existing impaired renal function. Such a combination should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated, and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Dual blockade (e.g. by adding an ACE inhibitor or aliskiren to angiotensin II receptor antagonists) should be limited to individual cases with careful monitoring of blood pressure, renal function and electrolytes. In some studies, dual blockade of the RAAS has been associated with a higher incidence of hypotension, syncope, hyperkalemia and changes in renal function (including acute renal failure) in patients with established atherosclerosis, heart failure or diabetes with organ damage, compared with the use of a single RAAS-acting agent. The combined administration of aliskiren with losartan is not recommended in patients with diabetes mellitus or in those with renal insufficiency (GFR 60 ml/min) (see Adverse Reactions).
Overdose
Symptoms of overdose. Data on overdose with losartan are limited. The most likely manifestations of overdose are hypotension and tachycardia; bradycardia may be due to parasympathetic (vagal) stimulation.
Treatment. Treatment depends on the length of time since taking the drug, as well as on the nature and severity of the symptoms. The priority measure should be to stabilize the function of the cardiovascular system. After oral administration of losartan, the use of activated charcoal in an appropriate dose is indicated. Later, the main vital signs of the body should be monitored frequently and adjusted if necessary. Losartan and its active metabolites are removed by hemodialysis.
Storage conditions
At a temperature not exceeding 25 °C in the original packaging.
