Amzaar

In patients with reduced blood volume (for example, those receiving treatment with large doses of diuretics) or with severe aortic stenosis, symptomatic arterial hypotension may occur. Correction of such conditions must be carried out before prescription or treatment must begin with a lower dose of the drug. Acute arterial hypotension is unlikely due to the gradual onset of action of the drug.

Based on pharmacokinetic data that showed a significant increase in plasma concentrations of losartan in patients with cirrhosis, patients with a history of impaired liver function should be prescribed lower doses of losartan.

Since amlodipine is primarily metabolized in the liver and has a half-life of 56 hours in patients with hepatic impairment, dosage titration should be gradual when administering amlodipine to patients with severe hepatic impairment.

Losartan

In patients with a history of angioedema (swelling of the face, lips, pharynx/larynx and/or tongue), monitoring of the use of the drug is necessary.

Embryotoxicity: Use of drugs that affect the RAAS during the second and third trimester of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in neonates include calvarial hypoplasia, anuria, hypotension, renal failure and death. If pregnancy is diagnosed, the drug should be discontinued immediately.

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.

While taking losartan, patients should not take potassium supplements or potassium-containing salt substitutes without prior consultation with their doctor.

Like all drugs that have a vasodilating effect, ARA II should be prescribed with caution to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Like all drugs that have a vasodilating effect, ARA II should be prescribed with caution to patients with coronary heart disease or cerebrovascular diseases, since an excessive decrease in blood pressure in patients in this group can lead to the development of myocardial infarction or stroke.

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 failure.

Since there is insufficient experience with the use of losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA functional class IV), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, losartan should be prescribed with caution in patients of these groups.

Since patients with primary hyperaldosteronism, as a rule, do not respond well to therapy with antihypertensive drugs that act by inhibiting the RAAS, the use of losartan is not recommended in patients in this group.

Data from pharmacokinetic studies indicate that the plasma concentration of losartan in patients with cirrhosis is significantly increased, therefore patients with a history of liver disease should be prescribed losartan at a lower dose. There is no experience with the use of losartan in patients with severe liver dysfunction, so the drug should not be used in patients in this group.

Due to inhibition of the RAAS, changes in renal function, including the development of renal failure, have been observed in some susceptible patients. These changes may subside after treatment is stopped.

Some drugs that affect the RAAS may increase blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney. Similar effects have been reported with losartan. Such renal dysfunction may be reversible after discontinuation of therapy.

Amlodipine

Unstable angina and acute myocardial infarction may occur after initiation of therapy or an increase in the dose of amlodipine, especially in patients with severe hypertrophic obstructive cardiomyopathy.

If oliguria or arterial hypotension develops in newborns whose mothers took Amzaar 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.

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, amlodipine therapy is usually recommended to begin with a dose of 2.5 mg once daily. Since Amzaar does not have a dosage containing amlodipine 2.5 mg, this dose should be prescribed in monotherapy with amlodipine.

No studies have been conducted to assess the effect on the ability to drive and operate machines, however, some of the undesirable effects observed with Amzaar may affect the ability to drive and operate machines.

Amzaar, 5 mg+100 mg, film-coated tablets, 30 pcs.

The hypotensive effect of Amzaar may be enhanced when used simultaneously with other antihypertensive drugs, therefore the simultaneous administration of different antihypertensive drugs should be justified.

Amlodipine

Can be safely used for the treatment of arterial hypertension together with thiazide diuretics, α-blockers or ACE inhibitors. Unlike other CCBs, a clinically significant interaction with amlodipine (III generation CCB) was not detected when used together with NSAIDs, incl. with indomethacin. It is possible to enhance the hypotensive effect of CCBs when used together with thiazide and loop diuretics, ACE inhibitors and nitrates, as well as to enhance their hypotensive effect when used together with α1-blockers and antipsychotics.

Concomitant use of amlodipine with CYP3A4 inhibitors requires careful monitoring of symptoms of hypotension and peripheral edema. When diltiazem 180 mg per day and amlodipine 5 mg per day were coadministered in elderly patients, the systemic exposure of amlodipine increases by 60%. Erythromycin, when used together, increases the Cmax of amlodipine in young patients by 22%, and in elderly patients by 50%. At the same time, strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to an even greater extent.

Despite the fact that an accurate quantitative assessment of the interaction between amlodipine and CYP3A4 inducers (for example, rifampicin, St. John's wort) has not been obtained, constant monitoring of blood pressure is recommended during their combined use. β-blockers, when administered simultaneously with amlodipine, can cause an exacerbation of heart failure.

Although negative inotropic effects have not generally been 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 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: enhancing the hypotensive effect of dihydropyridine derivatives.

With intravenous administration of dantrolene during treatment with amlodipine, collapse, arrhythmias, decreased strength of heart contractions and hyperkalemia are possible.

Calcium supplements may reduce the effect of CCBs.

When amlodipine is used together with lithium preparations, it is possible to increase the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Amlodipine does not change the pharmacokinetics of cyclosporine.

Does not affect the serum concentration of digoxin and its renal clearance.

Does not significantly affect 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.

Grapefruit juice: simultaneous single administration of 240 mg of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine.

Aluminum- or magnesium-containing antacids: their single dose 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, concomitant administration of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements, and potassium-containing salt substitutes may increase serum potassium levels. In some patients with impaired renal function who have been treated with NSAIDs, including selective COX-2 inhibitors, co-administration of ACE inhibitors and/or ARBs, including losartan, may cause further deterioration of renal function, leading to 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 blockers, including losartan. Therefore, the hypotensive effect of angiotensin II receptor antagonists may be weakened by the simultaneous use of NSAIDs, in particular selective COX-2 inhibitors. Thus, the simultaneous use of Amzaar with NSAIDs should be done with caution in patients with impaired renal function.

Double blockade of the RAAS

: It has been found that in patients with atherosclerosis, heart failure or diabetes with target organ damage, double blockade of the RAAS (simultaneous use of ACE inhibitors and ARB drugs) is associated with more frequent complications of therapy in the form of arterial hypotension, fainting (syncope), hyperkalemia and dysfunction kidney (including acute renal failure) compared with monotherapy with each drug. In this regard, combined treatment with ACE inhibitors and ARB drugs requires an individualized approach and constant monitoring of the functional activity of the kidneys.

There were no pharmacokinetically significant interactions of the drug with drugs such as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital.

Taking rifampin, an inducer of drug metabolism, reduces the concentrations of losartan and its active metabolite.

In humans, 2 inhibitors of the CYP3A4 isoenzyme have been studied. Ketoconazole does not affect the biotransformation of losartan administered intravenously to its active metabolite, and erythromycin does 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 and increases the concentration of losartan in the blood plasma, but the pharmacodynamic significance of the combined use of losartan and inhibitors of the CYP2C9 isoenzyme has not been established. It has been shown that individuals 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 biotransformation of losartan to its active metabolite is mediated predominantly by the CYP2C9 isoenzyme rather than by CYP3A4.

Contraindications

Stenosis of the aortic mouth with severe hemodynamic disturbances;
Severe liver failure (above 9 points on the Child-Pugh scale);
Shock;
Severe arterial hypotension;
Age up to 18 years;
Pregnancy and breastfeeding period;
Hypersensitivity to the components of the drug.

It is recommended to prescribe Amzaar with caution: to patients on a diet that limits salt intake, with hyperkalemia, renal failure (creatinine clearance (CC) less than 20 ml/min) or hemodialysis, liver failure (below 9 points on the Child-Pugh scale), arterial hypotension, mitral stenosis, aortic stenosis, sick sinus syndrome (SSNS) (tachycardia, severe bradycardia), hypertrophic obstructive cardiomyopathy, chronic heart failure of non-ischemic origin (II-IV functional class according to the NYHA classification), acute myocardial infarction (and during 4 weeks after it), with a reduced circulating blood volume (CBV) associated with taking high doses of diuretics, severe diarrhea, vomiting and other conditions causing hypovolemia in old age.

Directions for use and dosage

The tablets are taken orally 1 time per day with a small amount of water, regardless of meals.

The use of Amzaar should be started after preliminary titration of the doses of losartan and amlodipine. If necessary, you can switch to combination therapy from taking losartan or amlodipine separately.

When switching from simultaneous use of losartan and amlodipine, the dose of the drug is prescribed in accordance with the doses of the previous monotherapy.

The use of tablets is indicated for patients in whom similar doses of losartan (50 mg) or amlodipine (5 mg) do not sufficiently control blood pressure (BP).

In case of renal failure with CC 20-50 ml/min, patients do not require dose adjustment. When CC is less than 20 ml/min and hemodialysis, it is necessary to adjust the doses of the active components of the drug; prescribing Amzaar in this case is not recommended.

In patients taking diuretics in high doses, taking the drug is possible if sufficient volume replenishment is ensured, but only if it is not necessary to reduce the dose of losartan to 25 mg.

In case of liver failure (below 9 points on the Child-Pugh scale), the use of the drug is allowed if, in the opinion of the doctor, it is possible to prescribe losartan at a dose of 50 mg.

Over the age of 65 years, the drug is prescribed to patients with adequate tolerance to a dose of losartan 50 mg.

special instructions

Due to the risk of developing symptomatic arterial hypotension during the period of use of Amzaar, the patient's BCC deficiency should be eliminated before starting treatment.

Patients taking 25 mg of losartan per day are not recommended to prescribe a complex drug.

After discontinuation of amlodipine, caution should be exercised when prescribing another vasodilating agent; individually selecting the dose and dosing interval, it is necessary to monitor the patient's condition.

The use of amlodipine should be accompanied by an appropriate diet, control of body weight and salt intake, and strict dental hygiene. Regular visits to the dentist will help avoid bleeding, pain and gum hyperplasia.

Regular monitoring of plasma potassium levels is required when taking losartan, especially if renal function is impaired in elderly patients.

The drug may cause the development of hyperkalemia, so caution should be exercised if it is necessary to simultaneously prescribe potassium-sparing diuretics (including spironolactone, triamterene, amiloride), potassium-containing salt substitutes, potassium preparations, heparin and other drugs that increase the concentration of potassium in the blood plasma.

In patients with unilateral or bilateral renal artery stenosis, the use of losartan may cause a reversible increase in plasma urea nitrogen and creatinine concentrations.

Since the effect of the drug can cause dizziness, it is recommended to be careful when driving vehicles and machinery.

Cozaar®

Mechanism of action

Angiotensin II is a powerful vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and a decisive 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 has several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells. AT2 receptors are the second type of receptor to which angiotensin II binds, but its role in regulating cardiovascular function is unknown.

Losartan is a selective antagonist of angiotensin II AT1 receptors, highly effective when taken orally. 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 route of synthesis. Unlike some peptide angiotensin II antagonists, losartan does not have agonist properties.

Losartan selectively binds to AT1 receptors and does not bind to or block receptors of other hormones and ion channels that play an important role in regulating the function of the cardiovascular system. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), which is responsible for the destruction of bradykinin. Therefore, effects not directly related to AT1 receptor blockade, 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.

Pharmacodynamics

Losartan suppresses the increase in systolic and diastolic blood pressure (BP) during angiotensin II infusion. At the moment of reaching the maximum concentration of losartan in the blood plasma (Cmax) after taking losartan at a dose of 100 mg, the above effect of angiotensin II is suppressed by approximately 85%, and 24 hours after single and multiple doses - by 26-39%.

During the period of taking losartan, elimination of the negative feedback, which consists in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (PRA). An increase in ARP leads to an increase in the concentration of angiotensin II in the blood plasma. With long-term (6-week) treatment of patients with hypertension with losartan at a dose of 100 mg/day, a 2-3-fold increase in the concentration of angiotensin II in the blood plasma was observed at the time the losartan Cmax was reached. In some patients, an even greater increase in angiotensin II concentrations was observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, an antihypertensive effect and a decrease in plasma aldosterone concentrations appeared after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, ARP and angiotensin II concentrations decreased within 3 days to the values observed before the start of losartan administration. 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 an ACE inhibitor on angiotensin I, angiotensin II and bradykinin showed that losartan blocked 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. The ACE inhibitor blocked responses to angiotensin I and increased the effects due to bradykinin without affecting the response to angiotensin II, demonstrating a pharmacodynamic difference between losartan and ACE inhibitors.

Plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing dose of the drug. Since losartan and its active metabolite are angiotensin II receptor antagonists (ARA II), they both contribute to the antihypertensive effect.

In a study with a single dose of 100 mg of losartan, which included healthy volunteers (men), oral administration of the drug under high- and low-salt diets did not affect the glomerular filtration rate (GFR), effective renal plasma flow and filtration fraction. Losartan had a natriuretic effect that was more pronounced with a low-salt diet and did not appear to be associated with suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in renal excretion of uric acid.

In patients with hypertension, proteinuria (at least 2 g/24 hours), without diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, a significant decrease in proteinuria (by 42%), fractional excretion of albumin was observed and immunoglobulins (IgG). In these patients, losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with hypertension who took losartan at a dose of 50 mg for 4 weeks, there was no effect of therapy on the renal and systemic levels of prostaglandins.

Losartan does not affect autonomic reflexes and does not have a long-term effect on the concentration of norepinephrine in the blood plasma.

In patients with 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 cholesterol. At the same doses, losartan had no effect on fasting blood glucose concentrations.

The HEAAL clinical trial to evaluate the effect of high and low doses of ARB II (losartan) on the outcome of treatment in patients with chronic heart failure (CHF) included patients (n=3834) with CHF (II-IV functional class according to the NYHA classification) and intolerance to inhibitors APF. Patients were followed for more than 4 years (median follow-up 4.7 years) to compare the effects of losartan 50 mg/day and 150 mg/day on reducing all-cause mortality or hospitalization for heart failure. This study showed that losartan 150 mg/day significantly reduced the risk of all-cause mortality or hospitalization for heart failure compared with losartan 50 mg/day (hazard ratio [HR] 0.899, P = 0.027).

In general, losartan caused a decrease in serum uric acid concentrations (usually less than 0.4 mg/dL) that persisted during long-term treatment. In controlled clinical studies involving patients with hypertension, there were no cases of drug withdrawal due to an increase in creatinine concentration or potassium content in the blood serum.

A 12-week parallel study, which included patients with left ventricular failure (NYHA functional class II-IV), most of whom were taking 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 exhibited positive hemodynamic and neurohormonal effects, which persisted throughout the study. Hemodynamic effects included an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, as well as a decrease in total peripheral vascular resistance, mean systemic blood pressure, and heart rate. The incidence of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included decreased concentrations of aldosterone and norepinephrine in the blood.