Instructions for use LORTENZA®
The antihypertensive effect of Lortenza may be enhanced when used simultaneously with other antihypertensive drugs. Therefore, the simultaneous use of various antihypertensive drugs should be justified.
Amlodipine
The simultaneous use of amlodipine with thiazide diuretics, alpha-blockers or ACE inhibitors is considered safe.
Unlike other BMCCs, no clinically significant interaction with amlodipine (III generation BMCCs) was detected when used simultaneously with NSAIDs, incl. and with indomethacin.
It is possible to enhance the antihypertensive effect of BMCC when used simultaneously with thiazide and loop diuretics, ACE inhibitors and nitrates, as well as when used simultaneously with alpha1-blockers and antipsychotics.
Concomitant use of amlodipine with inhibitors of the CYP3A4 isoenzyme requires careful monitoring of symptoms of arterial hypotension and peripheral edema. With simultaneous use of diltiazem at a dose of 180 mg/day and amlodipine at a dose of 5 mg/day in elderly patients, the systemic exposure of amlodipine increases by 60%. Erythromycin, when used simultaneously, increases the Cmax of amlodipine in blood plasma in young patients by 22%, and in elderly patients by 50%. At the same time, strong inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to an even greater extent.
Despite the fact that an accurate quantitative assessment of the interaction between amlodipine and inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John's wort) has not been obtained, regular monitoring of blood pressure is recommended during their simultaneous use.
Beta-blockers, when used simultaneously with amlodipine, can cause an exacerbation of CHF.
Although negative inotropic effects have generally not been observed in amlodipine studies, some CBMCs may enhance the negative inotropic effects of antiarrhythmic drugs that prolong the QT interval (eg, amiodarone and quinidine).
A single dose of sildenafil in a dose of 100 mg in patients with arterial hypertension does not affect the pharmacokinetic parameters of amlodipine.
Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.
Ethanol (beverages containing alcohol):
- amlodipine with single and repeated use at a dose of 10 mg does not affect the pharmacokinetics of ethanol.
Neuroleptics and isoflurane enhance the antihypertensive effect of dihydropyridine derivatives.
With intravenous administration of dantrolene during therapy with amlodipine, collapse, arrhythmias, decreased strength of heart contractions and hyperkalemia are possible.
Calcium supplements may reduce the antihypertensive effect of BMCC.
With the simultaneous use of amlodipine with lithium preparations, an increase in the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.
Amlodipine does not change the pharmacokinetics of cyclosporine.
It has no effect on the serum concentration of digoxin and its renal clearance.
Does not significantly affect the effect of warfarin (prothrombin time).
Cimetidine does not affect the pharmacokinetics of amlodipine.
In in vitro studies, amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin and indomethacin.
A simultaneous single dose of 240 ml of grapefruit juice and amlodipine orally at a dose of 10 mg is not accompanied by a significant change in the pharmacokinetics of amlodipine.
A single dose of aluminum or magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine.
Losartan
As with the use of other drugs that block the formation of angiotensin II and its effects, the simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium supplements and potassium-containing salt substitutes may lead to an increase in serum potassium.
As with the use of other drugs that affect sodium excretion, losartan may reduce lithium excretion; therefore, when using lithium preparations and angiotensin II receptor antagonists simultaneously, it is necessary to carefully monitor the concentration of lithium in the blood serum.
In some patients with impaired renal function who have been treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists, including losartan, may cause a further deterioration of renal function, including the development of acute renal failure. Usually this effect is reversible. NSAIDs, including selective COX-2 inhibitors, may reduce the effect of angiotensin II receptor antagonists, including losartan. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be weakened by simultaneous use of NSAIDs, in particular selective COX-2 inhibitors. Thus, simultaneous use of the amlodipine/losartan combination with NSAIDs should be used with caution in patients with impaired renal function.
Dual blockade of the RAAS (simultaneous use of ACE inhibitors and angiotensin II receptor antagonists) in patients with atherosclerosis, CHF or diabetes mellitus with target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) in comparison with the use of a drug from one of the listed groups. Double blockade of the RAAS is possible only in selected cases under careful monitoring of renal function.
The simultaneous use of losartan with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (creatinine clearance less than 60 ml/min) and is not recommended in other patients.
There were no pharmacokinetically significant interactions between losartan and drugs such as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Taking rifampicin, an inducer of drug metabolism, reduces the concentrations of losartan and its active metabolite in the blood plasma.
In clinical studies, the use of two inhibitors of the CYP3A4 isoenzyme was studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect on the pharmacokinetics of losartan when administered orally.
Fluconazole, a CYP2C9 inhibitor, reduces the concentration of the active metabolite of losartan and increases the concentration of losartan in the blood plasma, but the pharmacodynamic significance of the simultaneous use of losartan and CYP2C9 inhibitors has not been established. It has been shown that patients whose body does not convert losartan into the active metabolite have a very rare and specific defect in the CYP2C9 isoenzyme. These data indicate that the metabolism of losartan to its active metabolite is mediated primarily by CYP2C9 rather than by CYP3A4.
Lortenza, 30 pcs., 10 mg+100 mg, film-coated tablets
The antihypertensive effect of Lortenza may be enhanced when used concomitantly with other antihypertensive agents. Therefore, the simultaneous use of various antihypertensive drugs should be justified.
Amlodipine
The simultaneous use of amlodipine with thiazide diuretics, alpha-blockers or ACE inhibitors is considered safe.
Unlike other CCBs, no clinically significant interaction with amlodipine (III generation CCB) was detected when used simultaneously with NSAIDs, incl. and indomethacin.
It is possible to enhance the antihypertensive effect of CCBs when used simultaneously with thiazide and loop diuretics, ACE inhibitors and nitrates, as well as when used simultaneously with alpha1-blockers and antipsychotics.
Concomitant use of amlodipine with inhibitors of the CYP3A4 isoenzyme requires careful monitoring of symptoms of arterial hypotension and peripheral edema. With simultaneous use of diltiazem at a dose of 180 mg/day and amlodipine at a dose of 5 mg/day in elderly patients, the systemic exposure of amlodipine increases by 60%.
Erythromycin, when used simultaneously, increases the Cmax of amlodipine in blood plasma in young patients by 22%, and in elderly patients by 50%. At the same time, strong inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to an even greater extent.
Despite the fact that an accurate quantitative assessment of the interaction between amlodipine and inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John's wort) has not been obtained, regular monitoring of blood pressure is recommended against the background of their simultaneous use.
Beta-blockers, when used simultaneously with amlodipine, can cause an exacerbation of CHF.
Although negative inotropic effects are not typically observed in amlodipine studies, some CCBs may enhance the negative inotropic effects of antiarrhythmic drugs that cause QT prolongation (eg, amiodarone and quinidine).
A single dose of 100 mg of sildenafil in patients with hypertension does not affect the pharmacokinetic parameters of amlodipine.
Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.
Ethanol (drinks containing alcohol): amlodipine with single and repeated use in a dose of 10 mg does not affect the pharmacokinetics of ethanol.
Neuroleptics and isoflurane enhance the antihypertensive effect of dihydropyridine derivatives.
With intravenous administration of dantrolene during therapy with amlodipine, collapse, arrhythmias, decreased strength of heart contractions and hyperkalemia are possible.
Calcium supplements may reduce the antihypertensive effect of CCBs.
With the simultaneous use of amlodipine with lithium preparations, an increase in the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible.
Amlodipine does not change the pharmacokinetics of cyclosporine.
Does not affect the serum concentration of digoxin and its renal clearance.
Does not have a significant effect on the action of warfarin (WW).
Cimetidine does not affect the pharmacokinetics of amlodipine.
in vitro studies
amlodipine does not affect the binding of digoxin, phenytoin, warfarin and indomethacin to plasma proteins.
A simultaneous single dose of 240 mg of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine.
A single dose of aluminum or magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine.
Losartan
As with the use of other drugs that block the formation of angiotensin II and its effects, the simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium supplements and potassium-containing salt substitutes may lead to an increase in serum potassium levels. As with the use of other drugs that affect sodium excretion, losartan can reduce the excretion of lithium, therefore, when using lithium preparations and ARA II simultaneously, it is necessary to carefully monitor the concentration of lithium in the blood serum.
In some patients with impaired renal function who have been treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of ACE inhibitors and/or ARB II, including losartan, may cause a further deterioration of renal function, leading to the development of acute renal failure (ARF). Usually this effect is reversible. NSAIDs, including selective COX-2 inhibitors, may reduce the effect of ARB II, including losartan. Therefore, the antihypertensive effect of ARA II may be weakened by simultaneous use of NSAIDs, in particular selective COX-2 inhibitors. Thus, the simultaneous use of amlodipine/losartan with NSAIDs should be used with caution in patients with impaired renal function.
Double blockade of the RAAS (simultaneous use of ACE inhibitors and ARB II) in patients with atherosclerosis, CHF or diabetes mellitus with target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with the use of a drug from one of the listed groups. Double blockade of the RAAS is possible only in selected cases with careful monitoring of renal function.
Concomitant use of losartan with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (creatinine clearance less than 60 ml/min) and is not recommended in other patients.
There were no pharmacokinetically significant interactions between losartan and drugs such as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital.
Taking rifampicin, an inducer of drug metabolism, reduces the concentrations of losartan and its active metabolite in the blood plasma.
In clinical studies, the use of two inhibitors of the CYP3A4 isoenzyme was studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan.
Erythromycin did not have a clinically significant effect on the pharmacokinetics of losartan when administered orally.
Fluconazole, an inhibitor of the CYP2C9 isoenzyme, reduces the concentration of the active metabolite of losartan and increases the concentration of losartan in the blood plasma, but the pharmacodynamic significance of the simultaneous use of losartan and inhibitors of the CYP2C9 isoenzyme has not been established. It has been shown that patients who do not metabolize losartan into the active metabolite have a very rare and specific defect in the CYP2C9 isoenzyme. These data indicate that the metabolism of losartan to its active metabolite is mediated primarily by CYP2C9 rather than by CYP3A4.
Lortenza®
Patients with reduced blood volume or severe aortic stenosis
In patients with reduced blood volume (for example, when taking high doses of diuretics, severe diarrhea, vomiting and other conditions leading to hypovolemia) or with severe aortic stenosis, symptomatic arterial hypotension may develop at the beginning of therapy with Lortenza®. Correction of such conditions should be carried out before starting therapy or treatment should be started with a lower dose of Lortenza®. For patients whose daily dose of losartan is 25 mg, the use of Lortenza® is not recommended (see section "Dosage and Administration").
Special instructions and precautions related to amlodipine
Due to the prolonged T1/2, vasodilation that develops as a result of taking amlodipine may persist even after its discontinuation. Thus, the use of another vasodilator after discontinuation of amlodipine should be done with caution, individual assessment of the dose, dosing interval and active monitoring of the patient's condition are necessary.
During the treatment period, it is necessary to control body weight and salt intake, and prescribe an appropriate diet. It is necessary to maintain dental hygiene and frequent visits to the dentist (to prevent soreness, bleeding and gum hyperplasia).
Unstable angina and myocardial infarction
After initiating therapy or increasing the dose of amlodipine, unstable angina and acute myocardial infarction may develop, especially in patients with severe HOCM.
Special instructions and precautions related to losartan
Hyperkalemia (plasma potassium content > 5.5 mmol/l) was observed in 1.5% of patients taking losartan as monotherapy. In none of these cases did the drug need to be discontinued. The simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium supplements, potassium-containing salt substitutes, as well as drugs that can lead to increased potassium levels in the blood plasma (for example, heparin) with losartan should be justified ( especially in elderly patients with impaired renal function), and the potassium content in the blood plasma should be monitored.
While taking losartan, patients should not take potassium supplements or table salt substitutes containing potassium without first consulting their doctor.
Taking losartan can lead to transient arterial hypotension, accompanied by shock, fainting and shortness of breath.
Lortenza® should be used with caution in patients:
— with reduced BCC;
- on a diet with limited salt.
Hypersensitivity reactions
In patients with a history of angioedema (swelling of the larynx, vocal cords, face, lips, pharynx and/or tongue), the use of Lortenza® should be carefully monitored (see section "Side effects").
Embryotoxicity
The use of drugs that affect the RAAS in the II-III trimesters of pregnancy reduces fetal renal function and increases the incidence of morbidity and mortality in the fetus and newborn. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformation. Possible adverse events in neonates include calvarial hypoplasia, anuria, hypotension, renal failure and death. If pregnancy is diagnosed, Lortenza® should be discontinued immediately (see section “Use during pregnancy and breastfeeding”).
Water-electrolyte imbalance
Fluid and electrolyte imbalance is common in patients with impaired renal function with or without diabetes mellitus, so careful monitoring of these patients is necessary. In clinical trials in patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the losartan group than in the placebo group. Several patients discontinued therapy due to hyperkalemia (see section “Side effects. Laboratory and instrumental data”).
Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy
Like all drugs that have a vasodilating effect, ARA II should be used with caution in patients with aortic or mitral stenosis, or HOCM.
Chronic heart failure
As with the use of other drugs that act on the RAAS, in patients with CHF and with or without impaired renal function, there is a risk of developing severe arterial hypotension or acute renal impairment.
Since there is insufficient experience with the use of losartan in patients with CHF and concomitant severe renal impairment, in patients with severe heart failure (NYHA functional class III-IV), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, Lortenza ® should be used with caution.
In patients with CHF of functional class III-IV (according to the NYHA classification) of non-ischemic origin, an increased incidence of pulmonary edema was observed during the use of amlodipine, despite the absence of signs of worsening heart failure.
Coronary heart disease and cerebrovascular diseases
Like all drugs that have a vasodilating effect, ARA II should be used with caution in patients with coronary artery disease or cerebrovascular diseases, since a pronounced decrease in blood pressure in this group of patients can lead to the development of myocardial infarction or stroke.
Primary hyperaldosteronism
Since patients with primary hyperaldosteronism generally do not respond well to antihypertensive drugs that act by inhibiting the RAAS, the use of Lortenza is not recommended in this group of patients.
Patients with liver failure
Data from pharmacokinetic studies indicate that patients with liver cirrhosis experience a significant increase in plasma concentrations of losartan. Lortenza should not be used in patients with severe hepatic impairment (Child-Pugh score greater than 9) or in patients with hepatic impairment (Child-Pugh score less than 9) in whom a dose reduction of losartan to 25 mg is recommended. day (see sections “Pharmacological properties. Pharmacokinetics”, “Contraindications”, “Dosage and administration”).
Since amlodipine is mainly metabolized in the liver and T1/2 in patients with impaired liver function is 56 hours, when prescribing amlodipine to patients with severe liver failure, dose titration should be carried out gradually.
Patients with kidney failure
Due to inhibition of the RAAS, some predisposed patients taking losartan experienced changes in renal function that were reversible when the drug was discontinued.
In patients whose renal function may depend on the activity of the RAAS (for example, with CHF III-IV functional class according to the NYHA classification), the use of ACE inhibitors was accompanied by oliguria and/or increasing azotemia and, rarely, acute renal failure and/or death. A similar picture was observed with the use of losartan in such patients. Some drugs that affect the RAAS may increase plasma urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney. A similar effect was observed when taking losartan in this group of patients; it was reversible when the drug was discontinued. Lortenza should be used with caution in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney.
Double blockade of the RAAS
Concomitant use of ARB II, including losartan, with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.
Concomitant use of ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Hypertensive crisis
The effectiveness and safety of use in hypertensive crisis have not been established.
Special patient groups
Children and teenagers
The effectiveness and safety of Lortenza® in children and adolescents under 18 years of age have not been established.
If oliguria or hypotension develops in newborns whose mothers took Lortenza during pregnancy, symptomatic therapy aimed at maintaining blood pressure and renal perfusion is necessary. Blood transfusions or dialysis may be required to prevent hypotension and/or maintain renal function.
Elderly patients
Clinical studies have not revealed any particularities regarding the safety and effectiveness of losartan in elderly patients (over 65 years of age). In elderly patients, due to reduced clearance leading to an increase in amlodipine AUC by approximately 40-60%, amlodipine therapy is usually recommended to begin with a dose of 2.5 mg once daily. Since Lortenza® does not have a dosage containing amlodipine 2.5 mg, this dose should be prescribed as amlodipine monotherapy.
Special information on excipients
Lortenza® contains lactose, so it should not be used for the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
Lortenza tablets p/o 100mg/10mg No. 10x3
Name
Lortenza tab., coated captivity. vol., 100 mg 10 mg per blister. in pack №10x3
Description
tab., cover film-coated 10 pcs. - blisters (3) - cardboard packs.
Main active ingredient
losartan + amlodipine
Release form
Tablets 100mg 10mg
Dosage
The drug is taken orally, 1 time/day, regardless of meal time, with a small amount of water. The recommended dose of Lortenza® is 1 tablet/day. The maximum daily dose is 10 mg + 100 mg. Patients taking losartan and amlodipine simultaneously can be switched to Lortenza®, containing losartan and amlodipine in the same doses. In patients with impaired renal function with CC from 50 to 20 ml/min, no dose adjustment is required. Lortenza® is contraindicated in patients with creatinine clearance less than 20 ml/min and in patients on hemodialysis. In patients with a history of impaired liver function (less than 9 points on the Child-Pugh scale), it is recommended to use losartan in lower doses. Due to the lack of a dosage containing 25 mg of losartan for the drug Lortenza®, this dose should be prescribed in monotherapy with losartan. The use of Lortenza® is possible in patients with impaired liver function (less than 9 points on the Child-Pugh scale), for whom, according to the doctor's decision, the use of losartan at a dose of 50 mg is recommended. In patients with reduced blood volume (for example, due to treatment with high doses of diuretics), the initial dose of losartan should be reduced to 25 mg 1 time / day. Due to the lack of a dosage containing 25 mg of losartan for the drug Lortenza®, this dose should be prescribed in monotherapy with losartan. Before using the drug Lortenza®, it is necessary to restore the blood volume and sodium content in the blood plasma. In elderly patients, no dose adjustment of Lortenza is required, but dose increases should be cautious. Lortenza® should not be prescribed to children and adolescents under the age of 18 years, because There are no data on the effectiveness and safety of use in this group of patients.
special instructions
Patients with reduced blood volume In patients with reduced blood volume (for example, when taking diuretics in high doses, severe diarrhea, vomiting and other conditions leading to hypovolemia), symptomatic arterial hypotension may develop at the beginning of therapy with Lortenza®. Before using Lortenza®, the BCC deficiency must be eliminated. For patients whose daily dose of losartan is 25 mg, the use of Lortenza® is not recommended. Precautions related to amlodipine Due to the prolonged T1/2, vasodilation that develops as a result of taking amlodipine may persist after its discontinuation. Therefore, the use of another vasodilator after discontinuation of amlodipine should be done with caution, with individual assessment of the dose, dosing interval and active monitoring of the patient's condition. During the treatment period, it is necessary to monitor body weight and salt intake, and an appropriate diet should be prescribed. It is necessary to maintain dental hygiene and frequent visits to the dentist (to prevent soreness, bleeding and gum hyperplasia). Precautions related to losartan Hyperkalemia (plasma potassium >5.5 mmol/L) was observed in 1.5% of patients taking losartan as monotherapy. In none of these cases did the drug need to be discontinued. The simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium supplements, potassium-containing salt substitutes, as well as drugs that can lead to increased potassium levels in the blood plasma (for example, heparin) with losartan should be justified ( especially in elderly patients with impaired renal function), and plasma potassium levels should be regularly monitored. Taking losartan can lead to transient arterial hypotension, accompanied by shock, fainting and shortness of breath. The drug Lortenza® should be used with caution in patients: with reduced blood volume; following a diet with limited salt. Hypersensitivity reactions: In patients with a history of angioedema (swelling of the larynx, vocal cords, face, lips, pharynx and/or tongue), the use of Lortenza® should be monitored. Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy As with all drugs that have a vasodilating effect, angiotensin II receptor antagonists should be used with caution in patients with aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy. Chronic heart failure As with the use of other drugs that act on the RAAS, in patients with CHF and with or without impaired renal function, there is a risk of developing severe hypotension or acute renal impairment. Because There is insufficient experience with the use of losartan in patients with CHF and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, Lortenza® should be used with caution in patients of these groups. IHD and cerebrovascular disease As with all drugs that have a vasodilating effect, angiotensin II receptor antagonists should be used with caution in patients with ischemic heart disease or cerebrovascular disease, since an excessive decrease in blood pressure in this group of patients can lead to the development of myocardial infarction or stroke. Primary hyperaldosteronism Because In patients with primary hyperaldosteronism, as a rule, there is no positive response to therapy with antihypertensive drugs that act by inhibiting the RAAS, the use of Lortenza® is not recommended in this group of patients. Patients with hepatic impairment Data from pharmacokinetic studies indicate that in patients with liver cirrhosis there is a significant increase in plasma concentrations of losartan. The use of Lortenza® is not recommended in patients with severe liver failure (more than 9 points on the Child-Pugh scale), as well as in patients with liver failure (less than 9 points on the Child-Pugh scale), who are recommended to reduce the dose of losartan to 25 mg/day. days Patients with renal failure Due to inhibition of the RAAS, some predisposed patients taking losartan experienced changes in renal function that were reversible when the drug was discontinued. In patients whose renal function may depend on the activity of the RAAS (for example, with CHF III-IV class according to the NYHA classification), the use of ACE inhibitors was accompanied by oliguria and/or increasing azotemia and, rarely, acute renal failure and/or death. A similar picture was observed with the use of losartan in such patients. In clinical studies, the use of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis led to an increase in the concentration of creatinine and residual urea nitrogen in the blood plasma. A similar effect was observed when taking losartan in this group of patients; it was reversible when the drug was discontinued. Lortenza should be used with caution in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney. Excipients Lortenza® contains lactose, therefore the drug should not be used for the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome. Effect on the ability to drive vehicles and operate machinery Care should be taken when driving vehicles and working with other technical devices that require increased concentration and speed of psychomotor reactions, taking into account the possibility of dizziness, headache, drowsiness, fatigue or nausea, especially at the beginning of treatment .
Pharmacodynamics
Lortenza is a combination of two active components with complementary antihypertensive effects: amlodipine (CCB) and losartan (angiotensin II receptor antagonist - ARA II). The active components of the drug have a different mechanism of antihypertensive action: amlodipine causes vasodilation, reducing peripheral vascular resistance, losartan affects the RAAS (inhibits the effects of angiotensin II), which leads to a more pronounced decrease in blood pressure compared to that during monotherapy with each drug. Amlodipine A dihydropyridine derivative, blocks calcium channels and reduces the transmembrane current of calcium ions into cardiomyocytes and vascular smooth muscle cells. The antihypertensive effect of amlodipine is associated with a direct relaxing effect on arterial smooth muscle. In preclinical studies, amlodipine had a more pronounced effect on vascular smooth muscle cells compared to cardiomyocytes. Amlodipine does not have a negative effect on either AV conduction or myocardial contractility. Reduces renal vascular resistance and increases renal blood flow. Studies of amlodipine in patients with CHF II–IV functional class according to the NYHA classification (New York Heart Association classification) showed that amlodipine does not have a negative effect on exercise tolerance, ejection fraction or plasma lipid and glucose concentrations. After a single oral dose of amlodipine, the effect begins within 2–4 hours and lasts for 24 hours. The maximum antihypertensive effect is achieved no earlier than 4 weeks after the start of therapy. Amlodipine reduces blood pressure in patients in a lying or sitting position, as well as during physical activity. Due to the gradual development of the pharmacodynamic effect, amlodipine does not cause a sharp decrease in blood pressure or reflex tachycardia. Amlodipine reduces the severity of left ventricular hypertrophy. Hemodynamic effects remain unchanged with long-term use of amlodipine. Losartan Synthetic ARA II (type AT1) for oral administration. Angiotensin II is a powerful vasoconstrictor, the main active hormone of the RAAS and an important determining pathophysiological link in the development of arterial hypertension (AH). Angiotensin II binds to AT1 receptors found in many tissues (vascular smooth muscle, adrenal glands, kidneys and heart) and performs important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of vascular smooth muscle cells. Losartan selectively blocks AT1 receptors. Losartan and its pharmacologically active carboxylated metabolite (E-3174), both in vitro and in vivo, block all physiological effects of angiotensin II, regardless of the source or route of its synthesis. Losartan does not have agonist properties and does not block the receptors of other hormones or ion channels involved in the regulation of cardiovascular activity. Losartan does not inhibit ACE, which destroys bradykinin. Accordingly, it does not cause an increase in the frequency of undesirable effects mediated by bradykinin. Suppression of the regulation of renin secretion by angiotensin II through a negative feedback mechanism during treatment with losartan causes an increase in plasma renin activity (PRA), which leads to an increase in the concentration of angiotensin II in the blood plasma. However, the antihypertensive effect and reduction in plasma aldosterone concentrations persist, indicating effective blockade of AT1 receptors. After stopping the use of losartan, blood ARP and the concentration of angiotensin II in the blood plasma decrease within 3 days to initial values.
Pharmacokinetics
Amlodipine Absorption. When taken orally in therapeutic doses, amlodipine is well absorbed. Cmax in blood plasma is achieved after 6–12 hours. Absolute bioavailability ranges from 64 to 80%. Food intake does not affect the absorption of amlodipine. Distribution. Vd is about 21 l/kg. Css in blood plasma is achieved 7–8 days after starting the drug. Binding to blood plasma proteins is 98%. Metabolism. Amlodipine undergoes slow but active metabolism in the liver with no significant first pass effect. Metabolites do not have significant pharmacological activity. Excretion. The final T1/2 from blood plasma is 30–40 hours. Plasma clearance is 7 ml/min/kg. Approximately 60% of metabolites and 10% of amlodipine unchanged are excreted by the kidneys, 20–25% through the intestines. Pharmacokinetics of special groups of patients Patients with impaired liver function. Experience with amlodipine in patients with impaired liver function is limited. In patients with impaired liver function, T1/2 prolongation is observed. Losartan Absorption. After oral administration, losartan is well absorbed. The systemic bioavailability of losartan when taken orally is approximately 33%. Cmax of losartan and its active metabolite in blood plasma is achieved after 1 and 3–4 hours, respectively. Distribution. Losartan and its active metabolite are 99% bound to plasma proteins (mainly albumin). Vd of losartan is 34 l. Metabolism. Losartan undergoes first pass metabolism through the liver to form an active carboxylated metabolite (E-3174) and other inactive metabolites. Approximately 14% of a dose of losartan administered intravenously or taken orally is converted into its active metabolite. Following oral or IV administration of radiocarbon-labeled losartan potassium (14C losartan), the majority of the radiolabel in the bloodstream was consistent with losartan and its active metabolite. A minimal level of biotransformation of losartan into its active metabolite was observed in approximately 1% of patients participating in clinical studies. Excretion. Plasma clearance of losartan and its active metabolite is 600 and 50 ml/min, respectively. The renal clearance of losartan and its active metabolite is 74 and 26 ml/min, respectively. When losartan is taken orally, about 4% of the dose is excreted unchanged by the kidneys and 6% of the dose is excreted by the kidneys in the form of an active metabolite. The pharmacokinetics of losartan and its active metabolite are linear when taken orally in doses up to 200 mg. When administered orally, the concentrations of losartan and its active metabolite in the blood plasma decrease polyexponentially with a final T1/2 of about 2 and 6–9 hours, respectively. At a dose of 100 mg taken once a day, neither losartan nor its active metabolite accumulates in the blood plasma. Losartan and its metabolites are excreted by the kidneys and through the intestines with bile. When 14C losartan was administered orally and intravenously in humans, about 35 and 43% of the radioactivity, respectively, of losartan and its active metabolite was excreted by the kidneys, 58 and 50%, respectively, through the intestines. Pharmacokinetics of special groups of patients Elderly patients. Concentrations of losartan and its active metabolite in blood plasma in elderly patients with hypertension do not differ significantly from these indicators in young patients with hypertension. Floor. Plasma concentrations of losartan in women with hypertension were 2 times higher than the corresponding values in men with hypertension. Concentrations of the active metabolite did not differ between men and women. Patients with impaired liver function. In patients with mild and moderate alcoholic cirrhosis of the liver, when taking losartan orally, the concentrations of losartan and its active metabolite in the blood plasma increased by 5 and 1.7 times, respectively, compared with similar indicators in young healthy male volunteers. Patients with impaired renal function. The concentration of losartan in blood plasma does not change in patients with creatinine Cl more than 10 ml/min. The AUC of losartan in patients on hemodialysis was approximately 2 times higher than the AUC of losartan in patients with normal renal function. Plasma concentrations of the active metabolite did not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite are not eliminated by hemodialysis.
Indications for use
Arterial hypertension (patients who are indicated for combination therapy with amlodipine and losartan).
Directions for use and doses
Orally, 1 time/day, regardless of the time of administration, write with a small amount of water. The recommended dose of Lortenza is 1 tablet/day. Lortenza at a dose of 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 Lortenza at a dose of 5 mg + 50 mg.
Use during pregnancy and lactation
Pregnancy The use of Lortenza® during pregnancy is contraindicated; if pregnancy occurs, you should immediately stop taking the drug. Medicines that affect the RAAS can cause damage and death to the fetus and newborn when used in pregnant women. Isolated cases of the use of ACE inhibitors during pregnancy have been described. The use of drugs that directly affect the RAAS in the second and third trimesters of pregnancy is associated with fetal damage and complications in newborns such as arterial hypotension, neonatal hypoplasia of the skull bones, anuria, reversible and irreversible renal failure. There have also been cases of oligohydramnios, presumably resulting from decreased renal function in the fetus. In these cases, oligohydramnios was associated with limb contractures, craniofacial deformities, and fetal lung hypoplasia. In addition, cases of premature birth, intrauterine growth restriction and patent ductus arteriosus have been reported, but no association with the use of angiotensin II receptor antagonists was found in these cases. The listed side effects do not appear to be a consequence of the use of angiotensin II receptor antagonists in the first trimester of pregnancy. Pregnant women who took angiotensin II receptor antagonists in the first trimester of pregnancy should be informed about the consequences of taking drugs of this group in the second and third trimesters of pregnancy. Depending on the stage of pregnancy, a stress test, a non-stress test, or a fetal biophysical profile can be used to assess the functional state of the fetus. Patients and physicians should be aware that oligohydramnios occurs when there is irreversible damage to the fetus. Newborns whose mothers took angiotensin II receptor antagonists during pregnancy should be under medical supervision, taking into account the risk of developing arterial hypotension, oliguria and hyperkalemia. With the development of oliguria, first of all, correction of blood pressure and renal perfusion is necessary. Exchange transfusion or hemodialysis is necessary to correct arterial hypotension and/or to replace renal function. Amlodipine The safety of amlodipine during pregnancy has not been established. In animal experiments, signs of reproductive toxicity were observed when amlodipine was used in high doses. The use of amlodipine during pregnancy is possible in the absence of safe antihypertensive alternative therapy, and if the potential benefit to the mother outweighs the possible risk to the fetus. Losartan The use of drugs acting on the RAAS in the second and third trimesters of pregnancy can cause serious damage or even death of the fetus, therefore, when planning pregnancy or when it occurs, you should stop taking losartan and, if necessary, transfer the patient to alternative antihypertensive therapy, taking into account security profile. Renal perfusion in the fetus, dependent on the RAAS, develops from the second trimester of pregnancy, so the risk to the fetus increases when taking losartan in the second and third trimesters of pregnancy. Lactation It is not known whether amlodipine and/or losartan is excreted in breast milk. In preclinical studies in animals, significant concentrations of amlodipine and/or the active metabolite of losartan in breast milk were observed. The use of Lortenza® is contraindicated during breastfeeding. Fertility Amlodipine In some patients, reversible biochemical changes in the head of the sperm were observed when using calcium channel blockers. There is insufficient clinical data on the potential effects of amlodipine on fertility. A rat study was reported to show side effects on the fertility of male rats. Losartan Mutagenic properties of losartan were not detected in in vitro and in vivo studies. Fertility and reproductive function of male rats receiving oral doses of up to 150 mg/kg/day did not change. When female rats were administered doses of 100 mg/kg/day or more, a decrease in the number of corpora lutea, implants, and embryos was observed.
Precautionary measures
Interaction with other drugs
The antihypertensive effect of Lortenza may be enhanced when used simultaneously with other antihypertensive drugs. Therefore, the simultaneous use of various antihypertensive drugs should be justified. Amlodipine Concomitant use of amlodipine with thiazide diuretics, alpha-blockers or ACE inhibitors is considered safe. Unlike other BMCCs, no clinically significant interaction with amlodipine (III generation BMCCs) was detected when used simultaneously with NSAIDs, incl. and with indomethacin. It is possible to enhance the antihypertensive effect of BMCC when used simultaneously with thiazide and loop diuretics, ACE inhibitors and nitrates, as well as when used simultaneously with alpha1-blockers and antipsychotics. Concomitant use of amlodipine with inhibitors of the CYP3A4 isoenzyme requires careful monitoring of symptoms of arterial hypotension and peripheral edema. With simultaneous use of diltiazem at a dose of 180 mg/day and amlodipine at a dose of 5 mg/day in elderly patients, the systemic exposure of amlodipine increases by 60%. Erythromycin, when used simultaneously, increases the Cmax of amlodipine in blood plasma in young patients by 22%, and in elderly patients by 50%. At the same time, strong inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to an even greater extent. Despite the fact that an accurate quantitative assessment of the interaction between amlodipine and inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John's wort) has not been obtained, regular monitoring of blood pressure is recommended during their simultaneous use. Beta-blockers, when used simultaneously with amlodipine, can cause an exacerbation of CHF. Although negative inotropic effects have generally not been observed in amlodipine studies, some CBMCs may enhance the negative inotropic effects of antiarrhythmic drugs that prolong the QT interval (eg, amiodarone and quinidine). A single dose of sildenafil in a dose of 100 mg in patients with arterial hypertension does not affect the pharmacokinetic parameters of amlodipine. Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin. Ethanol (drinks containing alcohol): amlodipine with single and repeated use in a dose of 10 mg does not affect the pharmacokinetics of ethanol. Neuroleptics and isoflurane enhance the antihypertensive effect of dihydropyridine derivatives. With intravenous administration of dantrolene during therapy with amlodipine, collapse, arrhythmias, decreased strength of heart contractions and hyperkalemia are possible. Calcium supplements may reduce the antihypertensive effect of BMCC. With the simultaneous use of amlodipine with lithium preparations, an increase in the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) is possible. Amlodipine does not change the pharmacokinetics of cyclosporine. It has no effect on the serum concentration of digoxin and its renal clearance. Does not significantly affect the effect of warfarin (prothrombin time). Cimetidine does not affect the pharmacokinetics of amlodipine. In in vitro studies, amlodipine does not affect the plasma protein binding of digoxin, phenytoin, warfarin and indomethacin. A simultaneous single dose of 240 ml of grapefruit juice and amlodipine orally at a dose of 10 mg is not accompanied by a significant change in the pharmacokinetics of amlodipine. A single dose of aluminum or magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine. Losartan As with other agents that block the formation of angiotensin II and its effects, the simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium supplements and potassium-containing salt substitutes may lead to an increase in serum potassium. As with the use of other drugs that affect sodium excretion, losartan may reduce lithium excretion; therefore, when using lithium preparations and angiotensin II receptor antagonists simultaneously, it is necessary to carefully monitor the concentration of lithium in the blood serum. In some patients with impaired renal function who have been treated with NSAIDs, including selective COX-2 inhibitors, concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists, including losartan, may cause a further deterioration of renal function, including the development of acute renal failure. Usually this effect is reversible. NSAIDs, including selective COX-2 inhibitors, may reduce the effect of angiotensin II receptor antagonists, including losartan. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be weakened by simultaneous use of NSAIDs, in particular selective COX-2 inhibitors. Thus, simultaneous use of the amlodipine/losartan combination with NSAIDs should be used with caution in patients with impaired renal function. Dual blockade of the RAAS (simultaneous use of ACE inhibitors and angiotensin II receptor antagonists) in patients with atherosclerosis, CHF or diabetes mellitus with target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) in comparison with the use of a drug from one of the listed groups. Double blockade of the RAAS is possible only in selected cases under careful monitoring of renal function. The simultaneous use of losartan with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (creatinine clearance less than 60 ml/min) and is not recommended in other patients. There were no pharmacokinetically significant interactions between losartan and drugs such as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Taking rifampicin, an inducer of drug metabolism, reduces the concentrations of losartan and its active metabolite in the blood plasma. In clinical studies, the use of two inhibitors of the CYP3A4 isoenzyme was studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect on the pharmacokinetics of losartan when administered orally. Fluconazole, a CYP2C9 inhibitor, reduces the concentration of the active metabolite of losartan and increases the concentration of losartan in the blood plasma, but the pharmacodynamic significance of the simultaneous use of losartan and CYP2C9 inhibitors has not been established. It has been shown that patients whose body does not convert losartan into the active metabolite have a very rare and specific defect in the CYP2C9 isoenzyme. These data indicate that the metabolism of losartan to its active metabolite is mediated primarily by CYP2C9 rather than by CYP3A4.
Contraindications
Severe liver failure (more than 9 points on the Child-Pugh scale); Hemodynamically pronounced stenosis of the aortic mouth; Hemodynamically unstable heart failure after acute myocardial infarction; Shock (including cardiogenic shock); Severe arterial hypotension (systolic blood pressure less than 90 mm Hg); Severe renal impairment (creatinine clearance less than 20 ml/min), use in patients on hemodialysis; Concomitant use with aliskiren in patients with diabetes mellitus or impaired renal function (creatinine clearance less than 60 ml/min); Pregnancy; Breastfeeding period; Age up to 18 years (efficacy and safety have not been established); Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome; Hypersensitivity to active ingredients and/or auxiliary components of the drug.
Compound
Amlodipine besilate (amlodipine besylate) 6.94 mg, equivalent to amlodipine - 5 mg, losartan A substance (granules) 327.1 mg, contains losartan potassium - 100 mg. Excipients: cellactose 80 (lactose monohydrate - 75%, cellulose - 25%) - 72.9 mg; MCC - 212.96 mg mg; pregelatinized starch - 54 mg; sodium carboxymethyl starch - 22 mg; iron dye yellow oxide (E172) - 0.4 mg; colloidal silicon dioxide - 2.1 mg; magnesium stearate - 6.6 mg.
Overdose
Cases of overdose with the fixed combination of amlodipine/losartan are unknown. Below is information about an overdose of amlodipine and losartan taken separately. Amlodipine Symptoms: marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including the development of shock and death). Treatment: administration of activated carbon (the use of activated carbon in healthy volunteers immediately or within 2 hours after oral administration of 10 mg of amlodipine led to a significant decrease in its absorption). If necessary, gastric lavage is indicated. Clinically significant arterial hypotension in case of an overdose of amlodipine requires a set of measures to normalize the state of the cardiovascular system, it is necessary to give an elevated position to the lower extremities, and constantly monitor the functional parameters of the heart and respiratory system, blood volume and diuresis. Intensive symptomatic therapy is carried out. To restore vascular tone and blood pressure, vasoconstrictor drugs are used (in the absence of contraindications to their use), in order to eliminate the blockade of calcium channels - intravenous administration of calcium gluconate. Hemodialysis is ineffective. Losartan There is limited data on overdose with losartan. Symptoms: marked decrease in blood pressure, tachycardia, bradycardia caused by parasympathetic (vagal) stimulation. Treatment: with the development of symptomatic arterial hypotension, maintenance therapy is carried out. Hemodialysis for losartan and its active metabolite is ineffective.
Side effect
WHO classification of the incidence of side effects: very often (?1/10), often (from?1/100 to
Storage conditions
The drug should be stored in its original packaging out of the reach of children at a temperature not exceeding 25°C.
