Expiration date: 02/2026
Active substance
losartan, amlodipine
Pharmacological action
The drug Lozap® AM
The results of the two bioequivalence studies involving healthy volunteers showed that the drug Lozap® AM in dosages of 5 mg+50 mg and 5 mg+100 mg bioequivalence of the combined use of appropriate doses of camsylate amlodipine and losartan potassium in the form of separate tablets.
Amlodipine
Bioequivalence of amlodipine and amlodipine besilate of camsilate was evaluated in a randomized-blind comparative study involving healthy volunteers. These study results showed that the tablets of camsylate amlodipine 5 mg tablets amlodipine bioequivalence of besilate 5 mg.
Mechanism of action
The drug Lozap® AM
The drug consists of two active substances with complementary mechanism of action to improve blood PRESSURE control in patients with hypertension: potassium losartan, angiotensin II receptor antagonist (ARA II), and amlodipine, a blocker of slow calcium channels (bmcc). Losartan blocks the vasoconstrictive effect of angiotensin II and stimulation of the latter release of aldosterone by selective inhibition of binding angiotensin II to AT1 receptors in many tissues. Amlodipine is a peripheral artery vasodilator that acts directly on the smooth muscles of the vessels, which leads to a decrease in peripheral vascular resistance and a decrease in blood PRESSURE.
Losartan
Angiotensin II is a powerful vasoconstrictor, the main active hormone of RAAS, as well as a decisive pathophysiological link in the development of hypertension. Angiotensin II binds to the AT1 receptors found in many tissues (smooth muscle, adrenal, kidney, and heart tissues) and performs several important biological functions, including vasoconstriction and the release of aldosterone. In addition, angiotensin II stimulates the growth of smooth muscle cells. AT2 receptors are the second type of receptors to which angiotensin II binds, but its role in the regulation of cardiovascular function is unknown.
Losartan is a selective antagonist OF angiotensin II AT1 receptors, highly effective when administered. Losartan and its pharmacologically active carboxylated metabolite (E-3174) both in vitro and in vivo block all physiological effects of angiotensin II regardless of its source or synthesis pathway. Unlike some peptide antagonists of angiotensin II, losartan does not have the properties of an agonist.
Losartan selectively binds to AT1-receptors and does not bind and does not block the receptors of other hormones and ion channels that play an important role in the regulation of cardiovascular function. In addition, losartan does not inhibit ACE (kininase II) responsible for the destruction of bradykinin. Therefore, effects not directly related to the blockade of AT1-receptors, such as increased bradykinin-mediated effects or the development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.
Amlodipine
Amlodipine is a dihydropyridine calcium antagonist (a calcium ion antagonist or slow channel blocker) that inhibits the transmembrane entry of calcium ions into smooth muscle cells of blood vessels and cardiomyocytes. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites on the receptors of slow calcium channels. The process of myocardial and vascular smooth muscle contraction depends on the transmembrane entry of extracellular calcium ions into the cell through specific ion channels. Amlodipine selectively inhibits the transmembrane entry of calcium, more affecting the cells smooth muscles receptacles, than cardiomiotita.
In vitro, a negative inotropic effect can be detected, but in studies on intact animals using amlodipine in therapeutic doses, this effect is not revealed. Amlodipine does not affect the serum calcium content. Within the physiological pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by gradual Association and dissociation with the binding site of the receptor, which leads to a gradual development of the effect.
Amlodipine is a peripheral artery vasodilator that acts directly on the smooth, vascular musculature, which leads to a decrease in peripheral vascular resistance and a decrease in blood PRESSURE.
Pharmacodynamics
The drug Lozap® AM
It is shown that the drug effectively reduces blood PRESSURE. Both losartan and amlodipine reduce blood pressure BY reducing peripheral resistance. Blocking the calcium intake into the cell and reducing the vasoconstricting effect caused by the action of angiotensin II are complementary mechanisms.
Losartan
Losartan inhibits the increase of systolic and diastolic blood PRESSURE in angiotensin II infusion. At the time of reaching Cmax of losartan in the blood plasma after administration of losartan at a dose of 100 mg of the above-mentioned effect of angiotensin II is suppressed by approximately 85% and 24 hours after single and multiple receptions - for 26-39%.
During the reception of losartan, the elimination of negative feedback, which consists in the suppression of angiotensin II secretion of renin, leads to an increase in the activity of blood plasma renin (ARP). Increasing ARP leads to an increase in the concentration of angiotensin II in blood plasma. Long-term (6-week) treatment of patients with hypertension losartan dose 100 mg/day observed 2-3-fold increase in the concentration of angiotensin II in plasma at the time of reaching Cmax losartan. Some patients had an even greater increase in the concentration of angiotensin II, especially with a short duration of treatment (2 weeks). Despite this, in the course of treatment the antihypertensive effect and reduce the concentration of aldosterone in blood plasma was shown after 2 and 6 weeks of treatment, indicating effective blockade of the angiotensin II receptor. After the abolition of losartan ARP and angiotensin II concentrations decreased for 3 days to the values observed before the start of the reception of losartan.
Since losartan is a specific antagonist of angiotensin II AT1-receptors, it does not inhibit ACE (kininase II) - an enzyme that inactivates bradykinin. A study comparing the effects of losartan at doses of 20 mg and 100 mg with the effects of ACE inhibitor on the effects of angiotensin I, angiotensin II and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin. This is due to the specific mechanism of action of losartan. ACE inhibitor blocked the response to angiotensin I and increased the severity of the effects caused by the action of bradykinin, without affecting the severity of the response to angiotensin II, which demonstrates the pharmacodiamical difference between losartan and ACE inhibitors.
The concentrations of losartan and its active metabolite in blood plasma, as well as the hypotensive effect of losartan increase with increasing dose. Since losartan and its active metabolite are antagonists of angiotensin II receptors, they both contribute to the antihypertensive effect.
In a study with a single dose of losartan at a dose of 100 mg, which included healthy volunteers (men), ingestion in a high - and low-salt diet did not affect GFR, effective renal plasma flow and filtration fraction. Losartan had a natriuretic effect, which was more pronounced in a low-salt diet and, apparently, was not associated with the suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in the excretion of uric acid by the kidneys.
In patients with hypertension, proteinuria (at least 2 g/24 h), without diabetes and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant decrease in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG). In these patients, losartan stabilized GFR and reduced the filtration fraction.
In postmenopausal women with hypertension, taking losartan at a dose of 50 mg for 4 weeks, there was no effect of therapy on renal and systemic prostaglandin levels.
Losartan does not affect vegetative reflexes and does not have a long-term effect on the concentration of noradrenaline in blood plasma.
In patients with arterial hypertension, losartan in doses up to 150 mg/day did not cause clinically significant changes in the concentration of fasting triglycerides, total cholesterol and high density lipoprotein. In the same doses, losartan did not affect the concentration of glucose in the blood on an empty stomach.
In General, losartan caused a decrease in the concentration of uric acid in the blood serum (usually less than 0.4 mg/DL), which remained with long-term treatment. In controlled clinical trials involving patients with hypertension, there were no reported cases of drug withdrawal due to an increase in creatinine concentration or potassium content in the blood serum.
In a 12-week parallel study, which included patients with left ventricular failure (II-IV functional class according to NYHA classification), most of whom took diuretics and/or cardiac glycosides, compared the effects of losartan at doses of 2.5, 10, 25 and 50 mg/day with placebo. At doses of 25 and 50 mg / day, the drug showed positive hemodynamic and neurohormonal effects, which persisted throughout the study. Hemodynamic effects included an increase in heart rate and decreased jamming pressure in the pulmonary capillaries, as well as a decrease in OPSS, mean systemic blood PRESSURE and heart rate. The frequency of arterial hypotension in these patients depended on the dose. Neurohormonal effects included reduction of aldosterone and noradrenaline concentrations in the blood.
Amlodipine
Hemodynamics. In patients with hypertension after receiving therapeutic doses of amlodipine causes vasodilation, which leads to a decrease in blood PRESSURE in the supine and standing positions. This decrease in blood pressure IS not accompanied by significant changes in heart rate or catecholamine plasma concentration with long-term administration. Despite the fact that in studies to assess hemodynamic parameters in patients with stable angina pectoris voltage at a single/in the administration of amlodipine was observed decrease in blood PRESSURE and increase in heart rate, in clinical studies multiple intake of amlodipine did not lead to clinically significant changes in heart rate or blood PRESSURE in normotensive patients with angina.
With long-term oral administration 1 time / day antihypertensive effect is maintained at least 24 no. amlodipine Concentration in blood plasma correlates with antihypertensive action in both young and elderly patients. The value of reduction in blood PRESSURE when taking amlodipine is also correlated with the severity of increase in blood PRESSURE before treatment. Thus, in patients with moderate hypertension (diastolic pressure 105-114 mm Hg. there was about 50% greater antihypertensive effect than in patients with mild hypertension (diastolic pressure 90-104 mm Hg.). V.). In patients with normal blood PRESSURE there was no clinically significant changes in blood pressure (+1/-2 mm Hg. V.).
In patients with hypertension and normal renal function, amlodipine in therapeutic doses decreased renal vascular resistance, increased GFR and effective renal plasma flow without changing the filtration fraction or proteinuria.
As with the use of other bmcc, the hemodynamic parameters of cardiac function at rest and under load (or pacing) in patients with normal ventricular function taking amlodipine generally showed a slight increase in the cardiac index without a significant change in the rate of increase in pressure in the left ventricular cavity at the beginning of the expulsion period (dP/dt) or final diastolic pressure or volume of the left ventricle. In studies to evaluate hemodynamic parameters amlodipine did not have a negative inotropic effect when used in therapeutic doses in healthy volunteers, even while using beta-blockers. However, similar results were observed in healthy volunteers or in patients with heart failure in the compensation stage with the use of drugs with a pronounced negative inotropic effect.
Electrophysiological effects. Amlodipine had no effect on sinoatrial node function or AV conduction in healthy volunteers. In patients with chronic stable angina pectoris, 10 mg of amlodipine did not significantly affect the a-N and H-V conductivity and recovery time of the sinus node after cardiac pacing. Similar results were obtained in patients, while taking amlodipine and beta-blockers. In clinical studies in which patients with hypertension or angina pectoris took amlodipine simultaneously with beta-blockers, there was no undesirable effect on electrocardiographic parameters. In clinical studies involving patients with angina alone, amlodipine therapy did not affect electrocardiographic intervals and did not cause AV blockade to a greater extent.
Pharmacokinetics
Losartan
Suction
When administered losartan is well absorbed and undergoes the effect of "first pass" through the liver to form an active carboxylated metabolite and inactive metabolites. System bioavailability of losartan in tablet form is about 33%. Mean Cmax of losartan and its active metabolite are achieved through 1 h and over 3-4 h respectively. When taking losartan in the course of a normal meal, clinically significant effect on the profile of the concentration of losartan in blood plasma was not revealed.
Distribution
Losartan and its active metabolite bind to plasma proteins (mainly albumin) by at least 99%. Vd losartan is 34 l. Studies on rats have shown that losartan is not practically penetrate through the GEB.
When the dosage of the drug 100 mg 1 time / day there is no significant accumulation in the blood plasma or losartan, or its active metabolite. Losartan and its active metabolite have linear pharmacokinetics when administered in doses of losartan to 200 mg.
Metabolism
About 14% of the dose of losartan in / in the introduction or ingestion is converted into its active metabolite. After ingestion or / in the introduction of radioactive carbon-labeled losartan (14C losartan) radioactivity circulating blood plasma, primarily due to the presence of losartan and its active metabolite. The low efficiency of losartan conversion into its active metabolite was observed in approximately 1% of the patients participating in the study. In addition to the active metabolite formed biologically inactive metabolites, including two main ones, formed as a result of side butyl chain hydroxylation, and one secondary - N-2-tetrazole-glucuronide.
Breeding
Plasma clearance of losartan and its active metabolite is about 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. When taking losartan inside about 4% of the dose is excreted by the kidneys unchanged and about 6% of the dose is excreted by the kidneys as an active metabolite.
After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with the final phase T1/2 about 2 hours and 6-9 hours, respectively.
The excretion of losartan and its metabolites is carried out by the kidneys and through the intestine with bile. After ingestion of 14C losartan in men, about 35% of radioactivity is found in urine and 58% in feces. After I/V administration of 14C losartan in men, approximately 43% of the radioactivity found in the urine and 50% in the feces.
Pharmacokinetics in special clinical cases
The concentrations of losartan and its active metabolite in blood plasma in elderly male patients with hypertension do not significantly differ from those in young male patients with hypertension.
The plasma concentrations of losartan in women with hypertension were 2 times higher than in men with hypertension. Concentrations of active metabolite in men and women did not differ. This is a clear pharmacokinetic difference, however, has no clinical significance.
When administered to patients with mild and moderate alcoholic cirrhosis of the liver, the concentration of losartan and its active metabolite in blood plasma were 5 and 1.7 times higher, respectively, than in young healthy male volunteers.
Plasma concentrations of losartan in patients with CC above 10 ml/min were no different from those in patients with unchanged renal function. The value of AUC losartan in patients on hemodialysis was approximately 2 times higher than the value of AUC losartan in patients with normal renal function. Concentrations of active metabolite in blood plasma did not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite are not removed by hemodialysis.
Amlodipine
Suction
After intake of therapeutic doses, amlodipine Cmax in plasma is reached after 6-12 h. the Absolute bioavailability of amlodipine is 64% -90% of the dose. Eating does not affect the bioavailability of amlodipine.
Distribution
Studies have shown that in patients with hypertension approximately 93% of the circulating drug binds to plasma proteins.
Css amlodipine in plasma is achieved after 7-8 days with daily intake.
Metabolism and excretion
Amlodipine intensively (about 90%) is metabolized into inactive metabolites in the liver. Kidneys displays 10% of the dose in the form of unchanged amlodipine and 60% as metabolites.
The excretion of amlodipine from the blood plasma occurs in two phases, the final phase of T1/2 is about 30-50 hours.
Pharmacokinetics in special clinical cases
Renal dysfunction does not significantly affect the pharmacokinetic parameters of amlodipine, therefore, patients with renal failure can be prescribed a normal initial dose of amlodipine.
In elderly patients and patients with hepatic insufficiency, amlodipine clearance is reduced, which leads to an increase in the AUC by about 40-60%. Such patients may require a lower initial dose of amlodipine. A similar increase in AUC was observed in patients with moderate or severe heart failure.
Pharmacokinetic studies involving patients with hypertension aged 6 to 17 years, who took amlodipine at a dose of 1.25 mg to 20 mg, showed that weight-adjusted clearance and Vd amlodipine were comparable to those in adult patients.
The drug Lozap® AM
The drug was not studied in any special groups of patients due to a good study of the active substances of the drug, losartan and amlodipine. Losartan should be used with caution in violation of kidney and liver function. It is contraindicated in pregnancy and breastfeeding. There were no separate studies involving children and elderly patients. Amlodipine should be used with caution in violation of liver function. It is contraindicated in the unstable course of cardiovascular diseases, as well as during pregnancy and breastfeeding.
Indications
- arterial hypertension (in patients, which shows the combined therapy).
Dosage regimen
The drug Lozap® AM is taken orally, regardless of meals, squeezed enough water.
The drug Lazap® AM can be taken in combination with other antihypertensive agents. Patients who have not achieved adequate control of blood PRESSURE with the use of losartan or amlodipine in monotherapy, can go to the combination therapy with Lapp® AM.
The recommended dose is 1 tab. 1 time/day
The maximum recommended dose is 5 mg+100 mg 1 time / day.
The drug Lozap ® AM at a dose of 5 mg+50 mg is prescribed to patients who have not achieved adequate blood PRESSURE control when using amlodipine at a dose of 5 mg or losartan at a dose of 50 mg in monotherapy.
The drug Lozap ® AM in the vine 5 mg + 100 mg is prescribed to patients who have not achieved adequate blood PRESSURE control when using losartan at a dose of 100 mg or the drug Lozap ® AM at a dose of 5 mg+50 mg.
Patients receiving combined therapy with amlodipine and losartan in the form of individual drugs can go to the combined drug Lozap ® AM (fixed dose combination containing the same dose of amlodipine and losartan) to increase adherence to therapy.
In patients with impaired renal function (CC 20-50 ml/min) dose adjustment is not required. Patients with moderate renal impairment are not recommended to use the drug. The use of the drug Lozap® AM is contraindicated in patients with severe renal impairment or patients on hemodialysis.
In case of therapeutic need for the use of the drug Lozap ® AM in patients with reduced BCC, patients with impaired liver function or elderly patients should conduct an individual selection of doses of active substances (amlodipine and losartan) prior to the use of a combined drug with fixed doses of active substances.
In patients with reduced BCC (eg, treated with diuretics in high doses), the recommended initial dose of losartan is 25 mg 1 time/day. Since the drug Lozap ® AM no dosage containing losartan 25 mg, monotherapy should be administered losartan.
The use of the drug Lozap ® AM is not recommended in patients with impaired liver function in history, which requires the appointment of losartan in low doses (ie 25 mg 1 time/day). Not studied the recommended dose of amlodipine in patients with impaired liver function of mild to moderate severity. Contraindicated use of the drug in patients with severe liver dysfunction.
In elderly patients due to reduced clearance amlodipine therapy is usually recommended to start with a dose of 2.5 mg 1 time / day. Since the drug Lozap ® AM no dosage containing amlodipine 2.5 mg, monotherapy should be prescribed amlodipine.
Since the efficacy and safety of the drug Lozap® AM in patients under the age of 18 years have not been studied, the use of the drug in this group of patients is contraindicated.
