Lortenza, 10 mg+50 mg 90 pcs

Hypotensive drug combined (slow calcium channel blocker + angiotensin II receptor antagonist)

Indications

Arterial hypertension (patients who are indicated for combination therapy with amlodipine and losartan).

Pharmacological effect

combined antihypertensive drug (slow calcium channel blocker + angiotensin II receptor antagonist)

Special instructions

Bilateral renal artery stenosis or stenosis of the artery of a single kidney, condition after kidney transplantation (no experience with use), coronary heart disease (CHD), heart failure with life-threatening arrhythmias, cerebrovascular diseases, primary hyperaldosteronism, history of angioedema, unstable angina, use in patients with low circulating blood volume (BCV) (for example, when using high doses diuretics, severe diarrhea, vomiting and other conditions leading to hypovolemia) – symptomatic hypotension may occur in patients on a salt-restricted diet, hyperkalemia, arterial hypotension, liver failure (less than 9 points on the Child-Pugh scale), sick sinus syndrome (severe bradycardia, tachycardia), heart failure with concomitant severe impaired renal function, severe CHF of non-ischemic etiology (III-IV functional class according to the NYHA classification), aortic and/or mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM), acute myocardial infarction (and within 1 month after a heart attack), simultaneous use with inhibitors and inducers of the CYP3A4 isoenzyme, water-electrolyte balance disorders, renal failure (mild to moderate), use in elderly patients.

Lortenza® should not be prescribed to children and adolescents under 18 years of age, as there is no data on the effectiveness and safety of use in this group of patients.

Renal dysfunction

When CC is 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.

Liver dysfunction

In patients with a history of liver dysfunction (less than 9 points on the Child-Pugh scale), lower doses of losartan are recommended. 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.

Elderly patients

In elderly patients (over 65 years of age), due to reduced clearance, amlodipine therapy is recommended to begin with a dose of 2.5 mg 1 time per day. Since Lortenza® does not have a dosage containing 2.5 mg amlodipine, this dose should be prescribed as amlodipine monotherapy.

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 preparations, 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 level in the blood plasma should be be under control.

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 blood volume;

· those 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. The drug Lortenza® should not be used 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 per 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.

Caution should be exercised when driving vehicles and working with other technical devices that require increased concentration and speed of psychomotor reactions, taking into account the risk of dizziness.

Active ingredient

Amlodipine, Losartan

Composition

for 1 tablet 5 mg + 50 mg

Core:

Active ingredients:

Amlodipine besilate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg

Losartan A, granule substance 163.55 mg, contains losartan potassium 50.00 mg

Excipients: cellactose 801, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, yellow iron oxide dye (E172), colloidal silicon dioxide, magnesium stearate

Film shell:

Opadry II white2, iron oxide dye yellow (E172), iron oxide dye red (E172)

for 1 tablet 5 mg + 100 mg

Core:

Active ingredients:

Amlodipine besilate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg

Losartan A, granule substance 327.10 mg, contains losartan potassium 100.00 mg

Excipients: cellactose 801, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, yellow iron oxide dye (E172), colloidal silicon dioxide, magnesium stearate

Film shell:

Opadry II white2, red iron oxide dye (E172)

for 1 tablet 10 mg + 50 mg

Core:

Active ingredients:

Amlodipine besilate (amlodipine besilate) 13.88 mg, equivalent to amlodipine 10.00 mg

Losartan A, granule substance 163.55 mg, contains losartan potassium 50.00 mg

Excipients: cellactose 801, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, yellow iron oxide dye (E172), colloidal silicon dioxide, magnesium stearate

Film shell:

Opadry II white2, red iron oxide dye (E172)

for 1 tablet 10 mg + 100 mg

Core:

Active ingredients:

Amlodipine besilate (amlodipine besilate) 13.88 mg, equivalent to amlodipine 10.00 mg

Losartan A, granule substance 327.10 mg, contains losartan potassium 100.00 mg

Excipients: cellactose 801, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, yellow iron oxide dye (E172), colloidal silicon dioxide, magnesium stearate

Film shell:

Opadry II white2, iron oxide yellow dye (E172)

1 Cellactose 80: lactose monohydrate, cellulose.

2 Opadry II white: polyvinyl alcohol, titanium dioxide (E171), macrogol, talc.

Pregnancy

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 retardation, and patent ductus arteriosus have been reported, but no association with the use of ARA II was found in these cases. The listed side effects do not appear to be a consequence of the use of ARA II in the first trimester of pregnancy. Pregnant women who took ARA II drugs in the first trimester of pregnancy must be informed about the consequences of taking ARA II drugs in the II and III trimesters of pregnancy.

Depending on the stage of pregnancy, to assess the functional state of the fetus, it is possible to use a stress test, a non-stress test, or determine the biophysical profile of the fetus. Patients and physicians should be aware that oligohydramnios occurs when there is irreversible damage to the fetus. Newborns whose mothers took ARA II 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 using high doses of amlodipine. 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, switch to alternative antihypertensive therapy, taking into account the safety 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.

Breastfeeding period

In preclinical studies in animals, significant concentrations of amlodipine and/or the active metabolite of losartan in breast milk were observed.

Amlodipine is excreted in breast milk. The proportion of the maternal dose received by the infant varies between 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

The use of Lortenza® is contraindicated during breastfeeding.

Fertility

Amlodipine

In some patients, when using BMCC, reversible biochemical changes in the sperm head were observed. 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

In in vitro and in vivo studies, the mutagenic properties of losartan were not detected. 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 corpus luteum, embryos and embryos was observed.

Contraindications

· Hypersensitivity to the active substances and/or auxiliary components of the drug.

· Pregnancy and breastfeeding (see section “Use during pregnancy and breastfeeding”).

· Severe liver failure (more than 9 points on the Child-Pugh scale).

· Obstruction of the outflow tract of the left ventricle (for example, hemodynamically severe aortic stenosis).

· Hemodynamically unstable heart failure after acute myocardial infarction.

· Shock (including cardiogenic shock).

· Age under 18 years (efficacy and safety have not been established).

· Severe arterial hypotension (systolic blood pressure less than 90 mm Hg).

· Severe renal dysfunction (creatinine clearance less than 20 ml/min), use in patients on hemodialysis.

Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area).
Concomitant use with ACE inhibitors in patients with diabetic nephropathy.

· Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Interaction

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 nonsteroidal anti-inflammatory drugs (NSAIDs), including 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 per day and amlodipine at a dose of 5 mg per 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, potent inhibitors of the CYP3A4 isoenzyme (ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to an even greater extent.

With simultaneous use of inducers of the CYP3A4 isoenzyme, the concentration of amlodipine in the blood plasma may vary. Thus, blood pressure control and dose adjustments of medications taken should be carried out both during and after their simultaneous use, especially in combination with powerful inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John’s wort preparations).

Beta-blockers, when used simultaneously with amlodipine, can cause an exacerbation of CHF.

Although negative inotropic effects have not generally been observed in amlodipine studies, some CBMCs 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. When amlodipine was taken simultaneously with sildenafil, each drug independently exerted its own antihypertensive effect.

Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg was 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.

When dantrolene is administered intravenously during amlodipine therapy, collapse, arrhythmias, decreased heart rate, 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.

It has no effect on the serum concentration of digoxin and its renal clearance.

Does not have a significant effect on the effect of warfarin (in particular, simultaneous administration of amlodipine and warfarin does not affect the increase in 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 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.

When used concomitantly with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood plasma, but the pharmacokinetic mechanism of this interaction has not been fully studied. To prevent the toxic effect of tacrolimus when used simultaneously with amlodipine, the concentration of tacrolimus in the blood plasma should be monitored and, if necessary, its dose should be adjusted.

Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. With simultaneous use of amlodipine and clarithromycin, the risk of developing arterial hypotension is increased. Close medical monitoring of patients receiving amlodipine concomitantly with clarithromycin is recommended.

Mammalian target of rapamycin (mTOR) inhibitors: mTOR inhibitors, such as sirolimus, temsirolimus, and everolimus, are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Drug interaction studies have not been conducted with cyclosporine and amlodipine in healthy volunteers or other patient populations, except for renal transplant patients in whom variable trough concentrations (mean values: 0-40%) of cyclosporine were observed. Concomitant use of amlodipine with cyclosporine may increase the concentration of cyclosporine in the blood plasma. With the simultaneous use of amlodipine in patients who have undergone kidney transplantation, the concentration of cyclosporine in the blood plasma should be monitored and, if necessary, its dose should be reduced.

Clinical interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Simultaneous repeated use of amlodipine at a dose of 10 mg and simvastatin at a dose of 80 mg leads to an increase in simvastatin exposure by 77%. The dose of simvastatin when used simultaneously with amlodipine should not exceed 20 mg once a day.

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 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 (for example, elderly or dehydrated patients, including those taking diuretics) who have been treated with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, concomitant use of ACE inhibitors and/or ARB II, including losartan, may cause a further deterioration of renal function, including 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, simultaneous use of the amlodipine/losartan combination with NSAIDs should be used with caution in patients with impaired renal function.

Double blockade of the RAAS is possible only in selected cases under careful monitoring of blood pressure, renal function and electrolyte levels in the blood plasma. In patients with atherosclerosis, CHF or diabetes mellitus with target organ damage, double blockade of the RAAS 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.

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.

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 its 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.

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.

Clinical pharmacology

Pharmacodynamics

Lortenza® is a combination of two active ingredients with complementary antihypertensive effects: amlodipine (slow calcium channel blocker (SCBC)) and losartan (angiotensin II receptor antagonist (ARA II)). The active ingredients of the drug have a different mechanism of antihypertensive action: amlodipine causes vasodilation, reducing total peripheral vascular resistance (TPVR), losartan affects the renin-angiotensin-aldosterone system (RAAS) (inhibits the effects of angiotensin II), which leads to a more pronounced decrease in blood pressure (BP) compared with that during monotherapy with each drug.

Amlodipine

Amlodipine, a dihydropyridine derivative, blocks “slow” 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 has no negative effect on either atrioventricular conduction or myocardial contractility. Reduces renal vascular resistance and increases renal blood flow.

Studies of amlodipine in patients with chronic heart failure (CHF) functional class II-IV 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 the “lying” and “sitting” positions, 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

Losartan is a 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 angiotensin-converting enzyme (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 under the influence of angiotensin II by the “negative” feedback mechanism during treatment with losartan causes an increase in plasma renin activity (PRA) in the blood, 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, the blood ARP and the concentration of angiotensin II in the blood plasma decrease within 3 days to the initial values.

Pharmacokinetics

Amlodipine

Suction

When taken orally in therapeutic doses, amlodipine is well absorbed. The maximum concentration (Cmax) in blood plasma is reached after 6-12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect the absorption of amlodipine.

Distribution

Volume of distribution (Vd) is approximately 21 l/kg. Equilibrium concentrations in blood plasma are achieved 7-8 days after starting the drug. Binding to blood plasma proteins – 98%.

Metabolism

Amlodipine undergoes slow but active metabolism in the liver with no significant first-pass effect. Metabolites do not have significant pharmacological activity.

Withdrawal

The final half-life (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 liver dysfunction

Experience with amlodipine in patients with impaired liver function is limited. In patients with impaired liver function, T1/2 prolongation is observed.

Losartan

Suction

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 hour and after 3-4 hours, respectively.

Distribution

Losartan and its active metabolite are 99% bound to blood 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 intravenous administration of radiocarbon-labeled losartan potassium (14C losartan), most of the radiolabel in the bloodstream was consistent with losartan and its active metabolite. The minimum level of biotransformation of losartan into its active metabolite was observed in approximately 1% of patients participating in clinical studies.

Withdrawal

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 74 ml/min 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 taken orally, the concentrations of losartan and its active metabolite in the blood plasma decrease polyexponentially with a final T1/2 of about 2 hours 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. After oral administration of 14C losartan in men, about 35% of the radioactivity is found in the urine and 58% in the feces. After intravenous administration of 14C losartan in men, approximately 43% of radioactivity is found in urine and 50% in feces.

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.

Gender

Concentrations of losartan in blood plasma in women with hypertension were 2 times higher than the corresponding values ​​in men with hypertension. The concentrations of the active metabolite did not differ between men and women.

Patients with liver dysfunction

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 to 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 clearance (CC) more than 10 ml/min. The area under the concentration-time curve (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.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of the reach of children.

Shelf life

2 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA-RUS, Russia