Presartan®
When taken orally, losartan is well absorbed from the gastrointestinal tract (GIT) and undergoes first-pass metabolism through the liver by carboxylation with the participation of the CYP2C9 isoenzyme to form an active metabolite.
The systemic bioavailability of losartan is approximately 33%.
The maximum concentration of losartan and its active metabolite is achieved in the blood serum approximately 1 hour and 3-4 hours after oral administration, respectively. Food intake does not affect the bioavailability of losartan. More than 9% of losartan and its active metabolite are bound to plasma proteins, mainly albumin. The volume of distribution of losartan is 34 l. Losartan practically does not penetrate the blood-brain barrier. Approximately 14% of losartan administered to a patient intravenously or orally is converted into an active metabolite. Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively. When taken orally, approximately 4% of the dose taken is excreted unchanged by the kidneys and about 6% is excreted by the kidneys in the form of an active metabolite. Losartan and its active metabolite exhibit linear pharmacokinetics when taken orally in doses up to 200 mg.
After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal half-life (T1/2) of losartan of about 2 hours, and of the active metabolite of about 6-9 hours. When taking the drug at a dose of 100 mg per day, neither losartan nor its active metabolite accumulates significantly in the blood plasma.
Losartan and its metabolites are excreted from the body through the intestines and kidneys. In healthy volunteers, after ingestion of the C14 isotope labeled losartan, about 35% of the radioactive label is found in the urine and 59% in the feces.
Pharmacokinetics in special groups of patients
In patients with mild to moderate alcoholic cirrhosis, the concentration of losartan was 5 times higher, and the active metabolite was 1.7 times higher than in healthy male volunteers.
When creatinine clearance (CC) is above 10 ml/min. the concentration of losartan in the blood plasma does not differ from that with normal renal function.
In hemodialysis patients, the area under the concentration-time curve (AUC) is approximately 2 times higher than in patients with normal renal function.
Neither losartan nor its active metabolite is removed from the body by hemodialysis.
Plasma concentrations of losartan and its active metabolite in elderly patients with arterial hypertension do not differ significantly from the values of these parameters in young male patients with arterial hypertension.
Plasma concentrations of losartan in women with arterial hypertension are 2 times higher than the corresponding values in men with arterial hypertension.
Concentrations of the active metabolite do not differ between men and women. This pharmacokinetic difference is not clinically significant.
Presartan tablets p/o 100 mg No. 14x2
Name
Presartan tablet cover p/o. 100 mg per bl. in pack No. 14x2
Description
Film-coated tablets, 100 mg: white or off-white, almond-shaped, biconvex film-coated tablets, embossed “100” on one side and embossed “B” on the other side.
Main active ingredient
Losartan
Release form
Pills
Dosage
100mg
pharmachologic effect
Pharmacodynamics
Losartan is a synthetic angiotensin II receptor (AT1 type) antagonist for oral use. Angiotensin II, a powerful vasoconstrictor, is an active hormone of the renin-angiotensin system and one of the most important factors in the pathophysiology of arterial hypertension. Angiotensin II binds to AT1 receptors, which are found in many tissues (eg, vascular smooth muscle, adrenal glands, kidneys and heart), mediating a number of important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells. Losartan selectively blocks AT1 receptors. In in vitro and in vivo studies, losartan and its pharmacologically active metabolite, carboxylic acid (E-3174), block all physiologically significant effects of angiotensin II, regardless of the source or route of synthesis. Losartan does not have an agonistic effect and does not block other hormone receptors or ion channels that are involved in the regulation of the cardiovascular system. Moreover, losartan does not inhibit ACE (kininase II), an enzyme that promotes the breakdown of bradykinin. As a result, there is no potentiation for bradykinin-mediated side effects. During the use of losartan, elimination of the negative feedback reaction of angiotensin II on renin secretion leads to an increase in plasma renin activity (PRA). This increase in activity leads to an increase in the level of angiotensin II in the blood plasma. Despite this increase, antihypertensive activity and a decrease in plasma aldosterone concentrations persist, 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 for AT2. The active metabolite is 10-40 times more active than losartan (based on weight).
Pharmacokinetics
Absorption After oral administration, losartan is well absorbed and undergoes first-pass metabolism to form the active metabolite carboxylic acid and other inactive metabolites. The systemic bioavailability of losartan in tablet form is approximately 33%. Average maximum concentrations of losartan and its active metabolite are reached after 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 liters. Biotransformation About 14% of losartan, when administered intravenously or orally, is converted into an active metabolite. After intravenous and oral administration of losartan potassium labeled with 14C, radioactivity in the blood plasma is usually characterized by losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was observed in approximately 1% of study participants. 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. The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively. When losartan is administered orally, approximately 4% of the dose is excreted unchanged in the urine, and approximately 6% of the dose is excreted in the urine as the active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral administration of losartan potassium in doses up to 200 mg. After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal half-life of approximately 2 hours and 6-9 hours, respectively. When used once a day at a dose of 100 mg, no pronounced accumulation of losartan and its active metabolite in the blood plasma is observed. Losartan and its active metabolite are excreted in bile and urine. Following oral and intravenous administration of 14C-labeled losartan, approximately 35 and 43% of the radioactivity is excreted in the urine and 58 and 50% in the feces, respectively. Pharmacokinetics in certain groups of patients Plasma concentrations of losartan and its active metabolite in elderly patients with arterial hypertension do not differ significantly from concentrations in young patients with arterial hypertension. Plasma concentrations of losartan are 2 times higher in women with arterial hypertension than in men. Concentrations of the active metabolite did not differ between men and women. In patients with mild and moderate alcoholic cirrhosis, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young men. Plasma concentrations of losartan did not change in patients with creatinine clearance above 10 ml/min. Compared with patients with normal renal function, the area under the concentration-time curve (AUC) is 2 times higher in patients undergoing hemodialysis. Plasma concentrations of the active metabolite do not change in patients with impaired renal function or in patients undergoing hemodialysis. Losartan and its active metabolite are not excreted from the body during hemodialysis.
Indications for use
Arterial hypertension; Chronic heart failure: treatment of chronic heart failure (in patients aged 60 years and older) when the use of ACE inhibitors is considered impossible due to incompatibility, especially with cough, or is contraindicated. Patients with heart failure whose condition has stabilized on an ACE inhibitor should not be switched to treatment with losartan. The patient must have a left ventricular ejection fraction ≤40%, be clinically stable, and adhere to the established treatment regimen for chronic heart failure
Directions for use and doses
For arterial hypertension, the initial daily dose is 25 mg, the average daily dose is 50 mg, the frequency of administration is 1 time/day. The maximum hypotensive effect develops 3-6 weeks after starting the drug. If necessary, the dose of the drug can be increased to 100 mg per day. In this case, it is possible to take the drug 2 times a day. The initial dose for patients with heart failure is 12.5 mg 1 time / day. Typically, the dose is titrated at weekly intervals (i.e., 12.5 mg/day, 25 mg/day, 50 mg/day) to a mean maintenance dose of 50 mg once a day, depending on the patient's tolerability. When prescribing the drug to patients receiving high doses of diuretics, the initial dose should be reduced to 25 mg 1 time / day. Patients with impaired liver function should be prescribed lower doses of losartan. In elderly patients, as well as patients with impaired renal function, including patients on hemodialysis, there is no need to adjust the initial dose of the drug. Presartan can be prescribed in combination with other antihypertensive drugs. Losartan can be taken regardless of food intake.
Use during pregnancy and lactation
Pregnancy Drugs that act directly on the renin-angiotensin system may cause damage to the developing fetus or death. If pregnancy is diagnosed, PRESARTAN should be discontinued immediately. The use of losartan is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. Epidemiological data regarding the risk of teratogenicity after use of ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a slight increase in risk cannot be ruled out. Since there are no controlled epidemiological data regarding the risk of angiotensin II receptor antagonists (ARAII), similar risks may exist for this class of drugs. Unless continued ARAII therapy is considered necessary, patients who are planning pregnancy should be given alternative hypertensive therapy with established safety profile for use during pregnancy. If pregnancy is diagnosed, treatment with losartan should be stopped immediately and, if necessary, alternative treatment should be initiated. It is known that the use of APAII during the second and third trimesters of pregnancy induces fetotoxicity (weakened renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If losartan was used during the second trimester of pregnancy, an ultrasound examination is recommended to check kidney function and the condition of the skull bones. The condition of newborns whose mothers have used losartan should be frequently monitored for the occurrence of arterial hypotension. Breastfeeding Since there is no information regarding the use of losartan during breastfeeding, the use of this drug is not recommended. It is preferable to alternative treatment with drugs with a better studied safety profile for use during breastfeeding, especially when feeding newborns and premature infants.
Precautionary measures
Fetal toxicity Use of drugs that affect the renin-angiotensin system during the second and third trimesters of pregnancy impairs fetal renal function and increases the incidence of fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with pulmonary hypoplasia and skeletal deformities in the fetus. Potential neonatal adverse reactions include calvarial hypoplasia, anuria, hypotension, renal failure and death. If pregnancy is established, use of the drug PRESARTAN should be stopped immediately (see section “Use during pregnancy and lactation”). Hypersensitivity Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be monitored frequently. Hypotension and fluid and electrolyte imbalance Symptomatic hypotension, especially after the first dose of the drug or after dose increases, may occur in patients with reduced intravascular volume and/or sodium deficiency caused by the use of strong diuretics, dietary salt restriction, diarrhea or vomiting. Before starting treatment with losartan, such conditions should be corrected or the drug should be used at a lower initial dose. Electrolyte imbalance Electrolyte imbalance is often observed in patients with impaired renal function (with or without diabetes mellitus) and should be taken into account. In a clinical study of patients with type 2 diabetes mellitus and nephropathy, the incidence of hyperkalemia was higher in the losartan group than in the placebo group. Therefore, plasma potassium concentrations and creatinine clearance values should be checked frequently, especially in patients with heart failure and a creatinine clearance of 30-50 ml/min. The simultaneous use of losartan and potassium-sparing diuretics, potassium supplements and salt substitutes containing potassium is not recommended. Impaired liver function Taking into account pharmacokinetic data indicating a significant increase in plasma concentrations of losartan in patients with cirrhosis, a dose reduction of the drug should be considered in patients with a history of impaired liver function. There is no experience with the use of losartan in patients with severe liver dysfunction. Therefore, losartan should not be used in patients with severe hepatic impairment. Impaired renal function Changes in renal function, including renal failure, associated with inhibition of the renin-angiotensin system have been reported (especially in patients with renal function dependent on the renin-angiotensin-aldosterone system, that is, patients with severe cardiac dysfunction or pre-existing cardiac dysfunction kidney). As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine levels have been reported in patients with bilateral renal artery stenosis or with arterial stenosis of a solitary kidney. These changes in renal function may be reversible after discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or arterial stenosis of a solitary kidney. Kidney transplantation There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Primary hyperaldosteronism In patients with primary hyperaldosteronism, antihypertensive drugs that act by inhibiting the renin-angiotensin system are generally ineffective. Therefore, the use of losartan is not recommended. Coronary artery disease and cerebrovascular disease As with other antihypertensive drugs, excessive reduction in blood pressure in patients with ischemic cardiovascular disease and cerebrovascular disease can lead to the development of myocardial infarction or stroke. Heart failure As with other drugs that affect the renin-angiotensin system, patients with heart failure with or without renal impairment are at risk of developing severe hypotension and (often acute) renal impairment. There is insufficient therapeutic experience with 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 cardiac arrhythmias. Therefore, losartan should be used with caution in this group of patients. Caution should be exercised when losartan and beta blockers are used concomitantly. Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy As with other vasodilators, the drug is prescribed with particular caution to patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Pregnancy Losartan should not be prescribed during pregnancy. If continued treatment with losartan is not considered essential, patients planning pregnancy should be prescribed an alternative antihypertensive agent with an established safety profile for use during pregnancy. If pregnancy is confirmed, treatment with losartan should be stopped immediately and, if necessary, alternative treatment initiated. Other Cautions and Warnings: As has been reported for ACE inhibitors, losartan and other angiotensin antagonists are less effective in black patients than in other patients, possibly due to the higher incidence of low renin activity in hypertensive patients who are black. Double blockade of the renin-angiotensin-aldosterone system (RAAS). There is evidence indicating an increased risk of hypotension, hyperkalemia and weakened renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see "Contraindications" and " interaction with other drugs"). If dual blockade is considered absolutely necessary, such therapy is carried out only under specialist supervision with frequent monitoring of renal function, electrolyte levels and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.
Interaction with other drugs
Other antihypertensive drugs may enhance the hypotensive effect of losartan. Concomitant use with other drugs that can induce arterial hypotension as an adverse reaction (tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension. Losartan is metabolized primarily through the cytochrome P450 (CYP) 2C9 system to an active carboxylic acid metabolite. In a clinical study, fluconazole (a CYP2C9 inhibitor) was found to reduce exposure to the active metabolite by approximately 50%. It has been established that simultaneous treatment with losartan and rifampicin (an inducer of metabolic enzymes) leads to a 40% decrease in the concentration of the active metabolite in the blood plasma. The clinical significance of this effect is unknown. There is no difference in exposure when losartan is co-administered with fluvastatin (a weak CYP2C9 inhibitor). As with other drugs that block angiotensin II or its effects, concomitant use of drugs that retain potassium in the body (eg, potassium-sparing diuretics: spironolactone, triamterene, amiloride) or may increase potassium levels (eg, heparin), and Also containing potassium supplements or salt substitutes may lead to an increase in serum potassium levels. The simultaneous use of such drugs is not recommended. A reversible increase in serum lithium concentrations, as well as toxicity, has been reported during concomitant use of lithium with ACE inhibitors. Cases have also been very rarely reported with the use of APAII. Concomitant treatment with lithium and losartan should be carried out with caution. If use of such a combination is considered necessary, it is recommended that serum lithium levels be monitored during concurrent use. With the simultaneous use of APAII and non-steroidal anti-inflammatory drugs (for example, selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid in doses that have an anti-inflammatory effect, non-selective NSAIDs), the antihypertensive effect may be weakened. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs may lead to an increased risk of deterioration of renal function, including the possible development of acute renal failure, as well as an increase in serum potassium levels, especially in patients with existing renal impairment. This 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. Double blockade of the renin-angiotensin-aldosterone system. Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) due to concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with an increased incidence of hypotension, hyperkalemia and decreased renal function (including acute renal failure), including comparison with monotherapy with a drug that affects the RAAS (see “Contraindications” and “Precautions”).
Contraindications
Hypersensitivity to the components of the drug; Children under 18 years of age; Pregnancy. Severe liver dysfunction. Concomitant use of angiotensin-converting enzyme inhibitors or ATP receptor blockers with Aliskiren in patients with diabetes mellitus or moderate/severe renal impairment (GFR)
Compound
Each film-coated tablet, 100 mg, contains: Active substance: Losartan potassium 100 mg Excipients: corn starch, microcrystalline cellulose, talc, colloidal silicon dioxide, sodium carboxymethyl starch, magnesium stearate; shell: hypromellose, titanium dioxide, macrogol-6000.
Overdose
Symptoms: arterial hypotension, tachycardia or bradycardia (due to excitation of the n.vagus). Treatment: symptomatic. Hemodialysis is not effective.
Side effect
The adverse reaction most commonly reported in clinical studies was dizziness. The frequency of adverse reactions listed below is defined as follows: very common ≥1/10; often ≥1/100 to 5.5 mmol/L) was observed in 1.5% of patients with hypertension. Chronic heart failure. From the nervous system: infrequently - dizziness, headache; rarely - paresthesia. From the heart: rarely - fainting, atrial fibrillation, stroke. From the vascular system: infrequently - arterial hypotension, including orthostatic hypotension. From the respiratory tract, chest and mediastinum: uncommon - shortness of breath. From the digestive tract: rarely - diarrhea, nausea, vomiting. From the skin and subcutaneous tissue: uncommon - urticaria, itching, rash. General condition and disorders associated with the method of administration of the drug: rarely - asthenia / weakness. Laboratory indicators: rarely - increased levels of urea, serum creatinine and serum potassium. The following adverse reactions occurred more frequently in patients treated with losartan than in patients in the placebo group. From the blood and lymphatic system: anemia. From the side of the heart: fainting, palpitation. From the vascular system: orthostatic hypotension. From the digestive tract: diarrhea. From the musculoskeletal system and connective tissue: back pain. From the kidneys and urinary tract: urinary tract infections. General condition and disorders associated with the method of administration of the drug: flu-like symptoms. Laboratory values: In a clinical study in patients with type II diabetes mellitus and nephropathy, hyperkalemia >5.5 mEq/L occurred in 9.9% of patients receiving losartan tablets and 3.4% of patients receiving placebo. Post-marketing observations. The following adverse reactions were reported during post-marketing surveillance. From the blood and lymphatic system: anemia, thrombocytopenia. From the organ of hearing and balance: ringing in the ears. From the immune system: rarely - hypersensitivity reactions (anaphylactic reactions, angioedema, including swelling of the larynx and glottis, which leads to airway obstruction and / or swelling of the face, lips, pharynx and / or tongue); some patients had a history of angioedema associated with the use of other drugs, including ACE inhibitors; vasculitis, including Henoch-Schönlein purpura. From the nervous system: migraine, dysgeusia. From the respiratory tract, chest and mediastinum: cough. From the digestive tract: diarrhea, pancreatitis, vomiting. General condition and disorders associated with the method of administration of the drug: malaise. From the digestive system: rarely - hepatitis, unknown - liver dysfunction. From the skin and subcutaneous tissue: urticaria, itching, rash, photosensitivity, erythroderma. From the musculoskeletal system and connective tissue: myalgia, arthralgia, rhabdomyolysis. From the reproductive system and mammary glands: erectile dysfunction/impotence. Renal and urinary tract: As a consequence of renin-angiotensin inhibition, changes in renal function have been reported, including renal failure in patients at risk; such renal changes may be reversible upon cessation of therapy. Mental disorders: depression. Laboratory indicators: hyponatremia.
Storage conditions
Store in a place protected from moisture and light, at a temperature not exceeding 25°C. Keep out of the reach of children.
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Instructions for use for Presartan tablet. cover p/o. 100 mg per bl. in pack No. 14x2
