Lozap AM, 5 mg+100 mg 30 pcs

Pharmacotherapeutic group:

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

ATC code:

C09DB06

Pharmacological properties

The drug Lozap® AM

The results of two bioequivalence studies with healthy volunteers showed that Lozap® AM at doses of 5 mg+50 mg and 5mg+100mg were bioequivalent to the combined use of the corresponding doses of amlodipine camisylate and potassium losartan as separate tablets.

Amlodipine

The bioequivalence of amlodipine besylate and amlodipine camsylate was evaluated in a randomized, blinded, cross-over comparative study involving healthy volunteers. The results of the study showed that amlodipine camsylate 5 mg tablets were bioequivalent to amlodipine besylate 5 mg tablets.

Mechanism of Action

Lozap® AM

Lozap® AM contains two active ingredients with complementary mechanisms of action to improve blood pressure (BP) control in patients with arterial hypertension (AH): potassium losartan, an angiotensin II receptor antagonist (ARA II), and amlodipine, a slow calcium channel blocker (CCB). Losartan blocks the vasoconstrictor effect of angiotensin II and its stimulation of aldosterone release by selective inhibition of angiotensin II binding to AT1 receptors in many tissues. Amlodipine is a vasodilator of peripheral arteries, which acts directly on vascular smooth muscle, resulting in reduction of peripheral vascular resistance and lowering of BP.

Lozartan

Angiotensin II is a potent vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and a crucial pathophysiological link in the development of AH. Angiotensin II binds to AT1 receptors located in many tissues (vascular smooth muscle tissues, adrenal glands, kidneys and heart) and has several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates smooth muscle cell overgrowth. AT1 receptors are the second type of receptors to which angiotensin II binds, but its role in the regulation of cardiovascular function is unknown.

Lozartan is a selective angiotensin II AT1-receptor antagonist that is 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 synthesis pathway. Unlike some peptide angiotensin II antagonists, losartan has no agonist properties.

Lozartan selectively binds to AT1 receptors and does not bind to or block receptors for other hormones and ion channels that play an important role in the regulation of cardiovascular function. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), which is responsible for bradykinin degradation. Consequently, 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 relevant to the action of losartan.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or “slow” channel blocker) that inhibits transmembrane entry of calcium ions into vascular smooth muscle cells and cardiomyocytes. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites on “slow” calcium channel receptors. The process of myocardial and vascular smooth muscle contraction depends on the transmembrane entry of extracellular calcium ions into the cell through specific ion channels. Amlodipine selectively inhibits transmembrane calcium entry, affecting vascular smooth muscle cells more than cardiomyocytes.

In vitro a negative inotropic effect can be detected, but in studies on intact animals using amlodipine at therapeutic doses this effect was not detected. Amlodipine has no effect on serum calcium content. Within the physiological pH interval amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by gradual association and dissociation from the receptor binding site, which leads to gradual development of the effect.

Amlodipine is a peripheral arterial vasodilator acting directly on vascular smooth muscle resulting in reduction of peripheral vascular resistance and lowering of BP.

Pharmacodynamics

Lozap® AM

Lozap® AM has been shown to effectively reduce BP. Both losartan and amlodipine lower BP by reducing peripheral resistance. Blocking calcium entry into the cell and reducing the vasoconstrictor effect due to angiotensin II exposure are complementary mechanisms.

Lozartan

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

While taking losartan, the elimination of the negative feedback of angiotensin II suppression of renin secretion leads to an increase in plasma renin activity (ARP). Increase of ARP leads to increase of angiotensin II concentration in blood plasma. During long-term (6-week) treatment of patients with AH with losartan at a dose of 100 mg/day, a 2-3-fold increase in plasma angiotensin II concentrations was observed when the Cmax of losartan was reached. In some patients, even greater increases in angiotensin II concentrations were observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, the antihypertensive effect and decreased plasma aldosterone concentrations were evident after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin I receptors. After withdrawal of losartan, ARP and angiotensin II concentration decreased within 3 days to values observed before initiation of losartan.

Because losartan is a specific angiotensin II AT1-receptor antagonist, it does not inhibit ACE (kininase II), the enzyme that inactivates bradykinin. A study comparing the effects of losartan at doses of 20 mg and 100 mg with those of an ACE inhibitor for effects on angiotensin I, angiotensin II, and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin. This is due to the specific mechanism of action of losartan. The ACE inhibitor blocked the response to angiotensin I and increased the severity of the bradykinin-dependent effects without affecting the severity of the response to angiotensin II, demonstrating the 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 drug dose. Since losartan and its active metabolite are angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.

In a study with a single 100-mg dose of losartan that included healthy volunteers (men), oral administration of the drug on a high-salt and low-salt diet had no effect on glomerular filtration rate (GFR), effective renal plasma flow, or filtration fraction. Losartan had a natriuretic effect that was more pronounced on the low-salt diet and did not appear to be associated with suppression of early sodium reabsorption in the proximal renal tubules. Lozartan also caused a transient increase in renal uric acid excretion. In patients with AH, proteinuria (at least 2 g/24 h), without diabetes mellitus and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant reduction in proteinuria (by 42%), fractional albumin and immunoglobulin (IgG) excretion. In these patients, losartan stabilized the FFR and decreased the filtration fraction.

In postmenopausal women with AH taking losartan at a dose of 50 mg for 4 weeks, there was no effect of therapy on renal and systemic prostaglandin levels.

Lozartan has no effect on autonomic reflexes and no lasting effect on plasma norepinephrine concentrations.

In patients with AH, losartan at doses up to 150 mg/day did not cause clinically significant changes in fasting triglyceride, total cholesterol, and high-density lipoprotein cholesterol concentrations. At the same doses, losartan had no effect on fasting blood glucose concentration.

In general, losartan caused a decrease in serum uric acid concentration (generally less than 0.4 mg/dL) that persisted with long-term treatment.

In controlled clinical trials involving patients with AH, there have been no reported cases of drug withdrawal due to increased serum creatinine or potassium concentrations.

In a 12-week parallel study that included patients with left ventricular failure (NYHA functional class II-IV), most of whom were taking diuretics and/or cardiac glycosides, the effects of losartan at doses of 2.5, 10, 25 and 50 mg/day were compared with placebo. At doses of 25 and 50 mg/day, the drug exhibited positive hemodynamic and neurohormonal effects that persisted throughout the study. Hemodynamic effects included increases in cardiac index and decreases in pulmonary capillary congestion pressure, as well as decreases in total peripheral vascular resistance, mean systemic BP, and heart rate (HR). The incidence of arterial hypotension in these patients was dose-dependent. Neurohormonal effects included decreases in aldosterone and norepinephrine blood concentrations.

Amlodipine

Hemodynamics

In patients with AH after therapeutic doses, amlodipine causes vasodilation, which leads to a decrease in BP in the supine and standing positions. This BP reduction is not accompanied by significant changes in HR or plasma catecholamine concentrations with long-term use. Although in studies evaluating hemodynamic parameters with patients with stable angina pectoris a decrease in BP and increase in HR were observed with single intravenous injection of amlodipine, in clinical trials multiple oral administration of amlodipine did not result in clinically significant changes in HR or BP in normotensive patients with angina pectoris.

Long-term oral administration once daily maintains antihypertensive effects for at least 24 hours. Plasma concentration of amlodipine correlates with antihypertensive effect in both young and elderly patients. The magnitude of BP reduction while taking amlodipine also correlates with the severity of BP increase before treatment. Thus, patients with moderately severe AH (diastolic pressure 105-114 mmHg) had approximately 50% greater antihypertensive effect than patients with mild AH (diastolic pressure 90-104 mmHg). No clinically significant BP change (+1/-2 mm Hg) was observed in patients with normal BP.

In patients with AH and normal renal function, administration of amlodipine at therapeutic doses resulted in decreased renal vascular resistance, increased FFR and effective renal plasma flow without changes in filtration fraction or proteinuria.

As with other BMCCs, hemodynamic parameters of cardiac function at rest and during exercise (or cardiac stimulation) in patients with normal ventricular function taking amlodipine generally showed a small increase in cardiac index without significant change in the rate of increase in left ventricular cavity pressure at the beginning of the ejection period (dP/dt) or left ventricular end diastolic pressure or volume. In studies assessing hemodynamic parameters, amlodipine had no negative inotropic effect when used at therapeutic doses in healthy volunteers, even when concomitantly used with beta-adrenoblockers. However, similar results were observed in healthy volunteers or in patients with compensated heart failure when using drugs with pronounced negative inotropic effect.

Electrophysiological effects

Amlodipine did not affect sinoatrial node function or atrioventricular conduction in healthy volunteers. In patients with chronic stable angina pectoris, intravenous administration of 10 mg of amlodipine had no significant effect on A-H and H-V conduction and time of sinus node recovery after cardiac stimulation. Similar results were obtained in patients taking amlodipine and beta-adrenoblockers simultaneously. In clinical trials in which patients with AH or angina pectoris took amlodipine concomitantly with beta-adrenoblockers, no adverse effect on electrocardiographic parameters was observed. In clinical trials involving patients with angina only, amlodipine therapy had no effect on electrocardiographic intervals and did not cause atrioventricular blockage to a greater extent.

Pharmacokinetics

Intake

Lozartan

. When ingested, losartan is well absorbed and is metabolized by “primary passage” through the liver to form the active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is about 33%. Mean maximum concentrations of losartan and its active metabolite are reached after 1 h and 3-4 h, respectively. No clinically significant effect on the plasma concentration profile of losartan has been identified when losartan is taken with a normal meal.

Amlodipine

After oral administration at therapeutic doses, the plasma concentration of amlodipine is reached after 6-12 h. Absolute bioavailability of amlodipine is 64% to 90% of the administered dose. Food intake does not affect the bioavailability of amlodipine.

Distribution

Lozartan

Lozartan and its active metabolite bind to plasma proteins (mainly to albumin) by at least 99%. The volume of distribution of losartan is 34 liters. Studies in rats have shown that losartan has almost no penetration through the blood-brain barrier.

Amlodipine

In studies, approximately 93% of the circulating drug has been shown to bind to plasma proteins in patients with AH.

Metabolism

Lozartan

About 14% of the dose of losartan is converted to its active metabolite by intravenous or oral administration. After intravenous or intravenous administration of radioactive carbon-labeled losartan (14C losartan), the radioactivity of circulating blood plasma is primarily due to the presence of losartan and its active metabolite. Low conversion efficiency of losartan to its active metabolite was observed in approximately 1% of patients participating in the study.

In addition to the active metabolite, biologically inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and one minor metabolite, N-2-tetrazol-glucuronide.

Amlodipine

Amlodipine is extensively (about 90%) metabolized to inactive metabolites in the liver. The kidneys excreted 10% of the taken dose as unchanged amlodipine and 60% as metabolites.

Lozartan

Plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, approximately 4% of the dose is excreted unchanged by the kidneys and approximately 6% of the dose is excreted as an active metabolite by the kidneys. Losartan and its active metabolite have linear pharmacokinetics with oral administration of losartan up to 200 mg. After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal phase half-life of approximately 2 and 6-9 hours, respectively. There is no significant plasma accumulation of either losartan or its active metabolite when the drug is dosed 100 mg once daily.

The excretion of losartan and its metabolites is by the kidneys and through the intestine with bile. After oral administration of 14C losartan in men, about 35% of radioactivity is found in urine and 58% in feces. After intravenous administration of 14C losartan in men, approximately 43% of radioactivity is detectable in urine and 50% in feces.

Amlodipine

Amlodipine is excreted from plasma in two phases, with a terminal phase half-life of approximately 30-50 h. The equilibrium plasma concentration of amlodipine is reached after 7-8 days with daily administration.

Pharmacokinetics in Special Patient Groups

Lozap® AM

Lozap® AM has not been studied in any special patient groups due to good knowledge of the active ingredients of the drug, losartan and amlodipine. Caution should be exercised with losartan if renal and hepatic function is impaired. It is contraindicated in pregnancy and during breastfeeding. There have been no separate studies involving pediatric patients and elderly patients.

Amlodipine should be used with caution if liver function is impaired. It is contraindicated in unstable cardiovascular disease and in pregnancy and during breastfeeding.

Lozartan

Elderly patients

Plasma concentrations of losartan and its active metabolite in elderly male patients with AH are not significantly different from those in younger male patients with AH.

Performance

Plasma concentrations of losartan in women with AH were twice as high as in men with AH. Concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference, however, has no clinical significance.

Patients with impaired liver function

In patients with mild to moderate alcoholic cirrhosis taking losartan orally, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, than in young healthy male volunteers.

Patients with impaired renal function

Plasma concentrations of losartan in patients with creatinine clearance above 10 mL/min were not different from those in patients with unchanged renal function. The area under the concentration-time curve (AUC) of losartan in patients on hemodialysis was approximately 2-fold greater compared to the AUC of losartan in patients with normal renal function. Plasma concentrations of the active metabolite were not altered in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite are not excreted by hemodialysis.

Amlodipine

Patients with impaired renal function

Impaired renal function has no significant effect on the pharmacokinetic parameters of amlodipine, so patients with renal impairment can be prescribed the usual starting dose of amlodipine.

Elderly patients and patients with hepatic impairment

In elderly patients and patients with hepatic impairment, the clearance of amlodipine is decreased, resulting in an increase in AUC of approximately 40-60%. These patients may require a lower starting dose of amlodipine. A similar increase in AUC has been observed in patients with moderate to severe heart failure.

Children and adolescents

Pharmacokinetic studies involving AH patients aged 6 to 17 years who were taking amlodipine at doses ranging from 1.25 mg to 20 mg showed that the body-weight-adjusted clearance and volume distribution of amlodipine were comparable to those in adult patients.

Indications

Active ingredient

How to take, the dosage

Lozap® AM is taken orally regardless of the time of eating.

It is recommended that the drug be taken with plenty of water.

Lozap® AM can be taken in combination with other hypotensive drugs. Patients who have not achieved adequate BP control with losartan or amlodipine monotherapy may switch to combination therapy with

Lozap® AM.

The recommended dose of Lozap® AM is 1 tablet once daily.

The maximum recommended dose of Lozap® AM is 5mg+100mg once daily.

Lozap® AM 5 mg+50 mg is indicated for patients who have not achieved adequate BP control with amlodipine 5 mg or losartan 50 mg in monotherapy.

Lozap® AM 5mg+100mg is indicated for patients who have not achieved adequate BP control with losartan 100 mg or Lozap® AM 5mg+50mg.

Patients taking amlodipine and losartan combination therapy as separate medications may switch to Lozap® AM combination therapy (a fixed dose combination containing the same doses of amlodipine and losartan) to improve adherence.

Patient use in patients with impaired renal function

In patients with impaired renal function (CKR 20-50 ml/min), no dose adjustment is required. In patients with moderate renal impairment the use of the drug is not recommended. The use of the drug Lozap® AM is contraindicated in patients with severe renal dysfunction or patients on hemodialysis.

In patients with reduced circulating blood volume (RBC), patients with impaired hepatic function or elderly patients when therapeutic necessity for use of Lozap® AM requires individual selection of the active ingredients (i.e. amlodipine and losartan) prior to initiation of fixed-dose combination therapy.

The use in patients with decreased blood circulation

In patients with decreased blood circulation (e.g., those treated with high doses of diuretics) the recommended starting dose of losartan is 25 mg once daily (see SPECIFICATIONS). Since Lozap® AM does not have a dose containing 25 mg losartan, this dose should be administered as losartan monotherapy.

The use in patients with hepatic impairment

The use of Lozap® AM is not recommended in patients with a history of hepatic impairment who require low-dose administration of losartan (ie, 25 mg once daily).

The recommended doses of amlodipine have not been studied in patients with mild to moderate hepatic impairment. Lozap® AM is contraindicated in patients with severe hepatic impairment.

Use in elderly patients

In elderly patients due to decreased clearance it is usually recommended to start amlodipine therapy with a dose of 2.5 mg once daily. Since Lozap® AM has no dosage containing amlodipine 2.5 mg, this dose should be administered in amlodipine monotherapy.

The use in children and adolescents

Because the efficacy and safety of Lozap® AM in patients less than 18 years of age has not been studied, Lozap® AM is contraindicated in this group of patients.

Interaction

Lozap® AM

There have been no studies of drug interactions of Lozap® AM with other medicinal products. Studies of drug interactions of active ingredients in Lozap® AM are described below.

Lozartan

There have been no clinically significant drug-drug interactions between losartan and hydrochlorothiazide, digoxin, warfarin, cimetidine, and phenobarbital in clinical studies of pharmacokinetic interactions. Rifampicin, as an inducer of drug metabolism, reduces the blood concentration of the active metabolite losartan. The use of two P450 CA4 isoenzyme inhibitors, ketoconazole and erythromycin, has been studied in clinical trials. Ketoconazole had no effect on the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin had no clinically significant effect with oral administration of losartan. Fluconazole, a P450 2C9 isoenzyme inhibitor, reduced the concentration of the active metabolite of losartan, but the pharmacodynamic significance of concomitant use of losartan and P450 2C9 isoenzyme inhibitors has not been studied. Patients who do not metabolize losartan to the active metabolite have been shown to have a very rare and specific defect in the P450 2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is by the P450 2C9 isoenzyme rather than by the P450 WA4 isoenzyme.

The concomitant use of losartan, as well as other drugs that block angiotensin II or its effects, with potassium-saving diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or potassium salts may result in increased serum potassium levels.

As with other drugs that affect lithium excretion, losartan may decrease lithium excretion, so serum lithium concentrations should be monitored closely when lithium and ARA II drugs are used concomitantly.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may decrease the effect of diuretics and other hypotensive agents. Consequently, the antihypertensive effect of ARA II or ACE inhibitors may be weakened when used simultaneously with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy, including selective COX-2 inhibitors, concomitant use of ARA II or ACE inhibitors may cause further impairment of renal function, including development of acute renal failure. These effects are usually reversible, therefore concomitant use of these drugs should be conducted with caution in patients with impaired renal function.

Double RAAS blockade with ARA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and impaired renal function (including acute renal failure) compared to monotherapy. Regular monitoring of BP, renal function and blood electrolytes in patients taking Lozap® AM and other drugs affecting the RAAS simultaneously is necessary. Lozap® AM should not be used concomitantly with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or impaired renal function (GFR less than 60 ml/min/1.73 m2).

Amlodipine

In vitro studies

In vitro studies have shown that amlodipine does not affect the binding of digoxin, phenytoin, warfarin and indomethacin to plasma proteins.

Cimetidine

The concomitant use of amlodipine and cimetidine has no effect on the pharmacokinetics of amlodipine.

Grapefruit juice

Concomitant administration of 240 mL grapefruit juice with a single oral dose of amlodipine 10 mg in healthy volunteers had no significant effect on amlodipine pharmacokinetics.

Antacids containing magnesium or aluminum hydroxide

Concomitant administration of an antacid containing magnesium or aluminum hydroxide with a single dose of amlodipine had no significant effect on amlodipine pharmacokinetics.

Sildenafil

Single-dose sildenafil at a dose of 100 mg in patients with AH had no effect on the pharmacokinetics of amlodipine. When amlodipine was taken simultaneously with sildenafil, each drug had its own antihypertensive effect independently.

Atorvastatin

Concomitant repeated administration of amlodipine at a dose of 10 mg with atorvastatin at a dose of 80 mg did not result in significant changes in equilibrium pharmacokinetic parameters of atorvastatin.

Simvastatin

Concomitant repeated administration of amlodipine at a dose of 10 mg with simvastatin at a dose of 80 mg resulted in a 77% increase in simvastatin exposure compared with the use of simvastatin in monotherapy. The dose of simvastatin in concomitant use with amlodipine should not exceed 20 mg once daily.

Digoxin

The concomitant use of amlodipine and digoxin did not lead to changes in digoxin blood concentrations or renal clearance of digoxin in healthy volunteers.

Ethanol (alcohol)

Single and multiple doses of amlodipine 10 mg had no significant effect on the pharmacokinetics of ethanol.

Warfarin

Concomitant administration of amlodipine and warfarin has no effect on increasing prothrombin time in response to warfarin administration.

CYP3A4 isoenzyme inhibitors

In elderly patients with AH concomitant use of diltiazem in daily dose of 180 mg and amlodipine in dose of 5 mg resulted in 1.6-fold increase of AUC of amlodipine. In healthy volunteers concomitant use of erythromycin and amlodipine has no significant effect on AUC of amlodipine, but strong CYP3A4 isoenzyme inhibitors (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent. Simultaneous use of amlodipine and CYP3A4 isoenzyme inhibitors should be regularly monitored for symptoms of arterial hypotension and edema.

CYP3A4 isoenzyme inducers

There are no data about significant effects of CYP3A4 isoenzyme inducers on pharmacokinetic parameters of amlodipine. The adequacy of clinical response in patients with concomitant use of amlodipine and CYP3A4 isoenzyme inducers should be monitored.

Special Instructions

Lozap® AM

Hypotension

Patients with decreased RBC (e.g., treated with high doses of diuretics) or with severe aortic stenosis may have symptomatic arterial hypotension. Correction of such conditions should be performed before prescribing Lozap® AM or starting treatment with a lower dose of Lozap® AM (see Dosage and Administration). Acute arterial hypotension is unlikely due to the gradual onset of action of the drug.

Hepatic impairment

Based on pharmacokinetic data that have shown significant increases in plasma concentrations of losartan in patients with cirrhosis, lower doses of losartan should be prescribed in patients with a history of hepatic impairment (see Pharmacological properties, Pharmacokinetics; Dosage and administration).

Because amlodipine is primarily metabolized in the liver and the half-life in patients with hepatic impairment is 56 h, when amlodipine is administered to patients with severe hepatic impairment, dose titration should be done gradually.

Lozartan

Hypersensitivity reactions

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

Embryotoxicity

The use of drugs acting on the RAAS in the second and third trimesters of pregnancy reduces fetal renal function and increases morbidity and mortality of the fetus and the newborn. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in neonates include skull bone hypoplasia, anuria, arterial hypotension, renal failure, and death. If diagnosed in pregnancy, Lozap® AM should be discontinued immediately (see Use in pregnancy and breastfeeding).

Water-electrolyte imbalance

Water-electrolyte imbalance is common in patients with impaired renal function with or without diabetes, so close monitoring of these patients is necessary. In clinical studies involving patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the group taking losartan than in the group taking placebo. Several patients discontinued therapy due to hyperkalemia (see SIDE ACTIVITY, Lab values).

Patients should not take potassium supplements or potassium-containing salt substitutes while taking losartan without first consulting a physician.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

As with all drugs with vasodilatory effects, APA II should be prescribed with caution in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Ischemic Heart Disease and Cerebrovascular Disease

As with all drugs with a vasodilator effect, APA II should be prescribed with caution in patients with ischemic heart disease or cerebrovascular disease, because excessive BP reduction in this group of patients may lead to myocardial infarction or stroke.

Chronic Heart Failure (CHF)

As with other drugs acting on the RAAS, patients with CHF and with or without impaired renal function are at risk of developing severe arterial hypotension or acute renal failure. Because 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), and in patients with heart failure and symptomatic life-threatening arrhythmias, losartan should be prescribed with caution in these groups.

Primary hyperaldosteronism

Because patients with primary hyperaldosteronism generally do not respond favorably to therapy with hypotensive agents that act by inhibiting the RAAS, the use of losartan is not recommended in this group of patients.

Hepatic impairment

The data from pharmacokinetic studies indicate that plasma concentrations of losartan are significantly increased in patients with cirrhosis, so patients with a history of liver disease should be prescribed losartan at a lower dose. There is no experience with losartan in patients with severe hepatic impairment, so the drug should not be used in this group of patients (see Pharmacological properties, Pharmacokinetics; Contraindications; Dosage and administration).

Renal dysfunction

Renal dysfunction, including the development of renal failure, has been observed in some predisposed patients due to inhibition of the RAAS.

These changes may go away after discontinuation of treatment.

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 the single kidney. Similar effects have been reported with losartan. Such renal dysfunction may be reversible after discontinuation of therapy.

Lozartan should be used with caution in patients with bilateral renal artery stenosis or renal artery stenosis of the single kidney.

Amlodipine

Unstable angina and myocardial infarction

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

Particular patient groups

Children and adolescents

The efficacy and safety of Lozap® AM in children and adolescents less than 18 years of age has not been established.

If neonates whose mothers have taken Lozap® AM during pregnancy develop oliguria or arterial hypotension, symptomatic therapy to maintain BP and renal perfusion should be given. Blood transfusion or dialysis may be required to prevent the development of arterial hypotension and/or to maintain renal function.

Patients in the Elderly

Clinical studies have not demonstrated any specific safety and efficacy of losartan in elderly patients (over 65 years of age).

In elderly patients, because of decreased clearance resulting in an increase in the AUC of amlodipine of approximately 40-60%, therapy with amlodipine is usually recommended to begin with a dose of 2.5 mg once daily. Since Lozap® AM does not have a dose containing amlodipine 2.5 mg, this dose should be administered in amlodipine monotherapy.

Influence on driving and operating ability

There have been no studies to evaluate the effect on driving and operating ability, but some adverse effects observed with Lozap® AM may affect driving and operating ability (see side effects).

Contraindications

Hypersensitivity to any of the ingredients of the drug.

Pregnancy and breast-feeding.

Age under 18 years (effectiveness and safety of use have not been established).

Simultaneous use with aliskiren or aliskiren-containing drugs in patients with diabetes mellitus and/or impaired renal function (GFR less than 60 mL/min/1.73 m2) (see INVERSE WITH OTHER MEDICINARY MEDICINATIONS).

Severe hepatic impairment (no experience).

Shock (including cardiogenic shock).

Left ventricular outflow tract obstruction (e.g., severe aortic stenosis).

Hemodynamically unstable heart failure after acute myocardial infarction.

The use in patients with impaired renal function (creatinine clearance less than 20 ml/min) or patients on hemodialysis.

With caution

Bilateral renal artery stenosis or artery stenosis of the sole kidney; hyperkalemia; post renal transplant condition (no history of use); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with associated severe renal dysfunction severe heart failure (NYHA functional class IV); heart failure with life-threatening arrhythmias; ischemic heart disease; cerebrovascular disease; primary hyperaldosteronism; history of angioedema; liver function impairment; unstable angina pectoris or myocardial infarction.

Patients with decreased circulating blood volume (e.g., those treated with high doses of diuretics)-symptomatic arterial hypotension may occur.

Side effects

The safety of Lozap® AM was evaluated in an 8-week clinical trial involving 646 patients with AH, of whom 325 patients were on amlodipine + losartan combination therapy. The following adverse events were observed in the clinical trials and were evaluated by the investigators as possibly, probably, or definitely related to taking the drug (frequent >1% and <10%; infrequent >0.1% and <1%).

Nervous system disorders
Frequent: dizziness, headache.
Infrequent: drowsiness.

General disorders
Infrequent: weakness, chest discomfort, chest pain, feeling of rapid satiety, peripheral edema.

Gastrointestinal tract
Infrequent: abdominal discomfort, dyspepsia, nausea, reflux esophagitis.

Skin and subcutaneous tissue
Infrequent: skin itching (generalized), urticaria (generalized).

Heart disorders
Infrequent: palpitations.

Vascular disorders
Infrequent: “rushes” of blood to the skin of the face, orthostatic hypotension.

Respiratory system, thorax and mediastinum
Infrequent: dyspnea.

Hearing organ and labyrinth disorders
Infrequent: vertigo.

Renal and urinary tract disorders
Infrequent: pollakiuria.

The following adverse events have been observed when using the active ingredients in Lozap® AM in monotherapy.

Lozartan

Because clinical trials are conducted under different conditions, the frequency of adverse reactions observed in clinical trials of one drug cannot be directly compared with the frequency of adverse reactions observed in clinical trials of another drug and cannot reflect the frequency observed in clinical practice.

In general, losartan is well tolerated in patients with AH. Adverse events are mild and transient and do not require discontinuation of therapy. The cumulative incidence of adverse events when taking losartan is comparable to that of placebo. In controlled trials, the rate of therapy withdrawal due to clinically significant adverse events was 2.3% in losartan group and 3.7% in placebo group.

In controlled clinical trials of losartan in patients with AH, the only adverse reaction associated with treatment and observed more frequently than with placebo was dizziness, observed in the losartan treatment groups with a frequency of 1% or more. In addition, dose-dependent orthostatic reactions were observed in less than 1% of patients. Rarely (>0.01% and <0.1% of cases) a skin rash was reported, but the incidence was less than with placebo.
In double-blind controlled clinical trials, the following adverse events were observed in >1% of patients with AH on losartan (n=2085) or placebo (n=535) regardless of their association with treatment.

General disorders: stomach pain 1.7% (placebo 1.7%); weakness and increased fatigue 3.8% (3.9%); chest pain 1.1% (2.6%); peripheral edema 1.7% (1.9%).

Cardiovascular system: palpitations 1.0% (placebo 0.4%); tachycardia 1.0% (1.7%).

Digestive system: diarrhea 1.9% (placebo 1.9%); dyspepsia 1.1% (1.5%); nausea 1.8% (2.8%).

Musculoskeletal side: back pain 1.6% (placebo 1.1%); muscle cramps 1.0% (1.1%).

Central nervous system: dizziness 4.1% (placebo 2.4%); headache 14.1% (17.2%); insomnia 1.1% (0.7%).

Respiratory system: cough 3.1% (placebo 2.6%); nasal mucosal edema 1.3% (1.1%); pharyngitis 1.5% (2.6%); sinusitis 1.0% (1.3%); upper respiratory infections 6.5% (5.6%).

Controlled clinical trials have shown that losartan is generally well tolerated in patients with AH and left ventricular hypertrophy. The most common adverse reactions associated with taking losartan were systemic and non-systemic dizziness and asthenia/weakness.

In this study, patients without a history of diabetes mellitus had a lower incidence of new diabetes mellitus with losartan compared with atenolol (p < 0.001). Because there was no placebo patient group in this study, it is unknown whether this is a positive effect of losartan or an adverse effect of atenolol.

Controlled clinical trials have shown that losartan is generally well tolerated in patients with type 2 diabetes mellitus and proteinuria. The most common adverse reactions associated with administration of losartan were dizziness, asthenia/weakness, marked BP decrease, and hyperkalemia (see DISCUSSION NOTES).

The following adverse reactions have been observed in clinical practice during the post-registration period.

Hypersensitivity reactions: Anaphylactic reactions, angioedema with involvement of the larynx and pharynx causing airway obstruction, and/or angioedema of the face, lips, pharynx and/or tongue were rarely observed in patients taking losartan. Some of these patients had a history of angioedema when taking other drugs, including ACE inhibitors. Rarely, the occurrence of vasculitis, including Schoenlein-Henoch purpura, has been reported.

Digestive system disorders: hepatitis (rare), impaired liver function, vomiting.

General disorders: feeling of general discomfort.

Blood system: anemia, thrombocytopenia (rare).

Musculoskeletal system: myalgia, arthralgia.

Central nervous system: migraine, dysgeusia.

Genital and mammary system disorders: erectile dysfunction/impotence.

Respiratory system: cough.

Skin disorders: urticaria, skin itching, skin redness, photosensitization.

Amlodipine besylate

. Because clinical studies are conducted under different conditions, the frequency of adverse reactions observed in clinical trials of one drug cannot be directly compared with the frequency of adverse reactions observed in clinical trials of another drug and cannot reflect the frequency observed in clinical practice.

The safety of amlodipine besylate has been evaluated in clinical trials involving more than 11,000 patients. In general, treatment with amlodipine besylate in doses up to 10 mg once daily was well tolerated. Most of the adverse events observed during therapy with amlodipine besylate were mild to moderate in severity.

In controlled clinical trials directly comparing amlodipine besylate therapy in doses up to 10 mg once daily with placebo, withdrawal of amlodipine besylate therapy due to adverse events was required in only 1.5% of patients, which was not significantly different from placebo group (about 1%). The most frequent (>1% and <10%) adverse events were headache and edema.

The following frequency (%) of dose-dependent adverse events were observed:

Other adverse events that were observed in placebo-controlled clinical trials in more than 1.0% of patients and had no clear relationship to dose:

Some adverse events, apparently related to amlodipine besylate administration and dose, were observed more frequently in women than in men:

The following adverse events frequently (>0.1% and <1%) were observed in patients in controlled clinical trials or in open studies or in the post-registration period of use when causality is unknown (indicated to inform possible causality):

Cardiovascular system: arrhythmias (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, marked decrease in BP, ischemic peripheral vascular disorders, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

Central and peripheral nervous system disorders: hypoesthesia, peripheral neuropathy, paresthesia, tremor, vertigo.

Digestive system disorders: anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gum hyperplasia.

General disorders: allergic reaction, asthenia*, back pain, “rushes” of blood to the skin of the face, malaise, pain, stiffness, weight gain, weight loss.

Musculoskeletal system disorders: arthralgia, arthrosis, muscle cramps*, myalgia.

Psychiatric disorders: sexual dysfunction (in men* and women), insomnia, increased excitability, depression, unusual dreams, anxiety, depersonalization.

Respiratory system: shortness of breath*, nasal bleeding.

Skin disorders: angioedema, erythema multiforme, itching*, skin rash*, erythematous rash, maculopapular rash.

Senses: visual impairment, conjunctivitis, diplopia, pain in the eye, tinnitus.

Urinary system disorders: frequent urination, impaired urination, nicturia.

Autonomic nervous system disorders: dry mouth, increased sweating.

Metabolism and nutrition: hyperglycemia, thirst.

Hematopoietic disorders: leukopenia, purpura, thrombocytopenia.

* These adverse events were seen in less than 1% in placebo-controlled studies, but their incidence was 1% to 2% in all studies with multiple uses of amlodipine.

The following adverse events were observed very rarely (<0.1%): Heart failure, rhythm disturbances, extrasystole, skin depigmentation, urticaria, dry skin, alopecia, dermatitis, muscle weakness, muscle twitching, ataxia, increased BP, migraine, decreased skin temperature and moisture, apathy, agitation, amnesia, gastritis, increased appetite, frequent loose stools, cough, rhinitis, dysuria, polyuria, parosmia, taste disorder, accommodation disorder, and xerophthalmia.

Other adverse events have been observed sporadically, and no causal relationship to drug intake or comorbidities, such as myocardial infarction and angina pectoris, could be established.

The following adverse events were also observed during the post-registration follow-up period. Because these adverse reactions were obtained voluntarily from a population of unknown size, it is not always possible to reliably determine their frequency or establish a causal relationship with drug administration.

An adverse event that was observed infrequently in the post-registration follow-up period without an established causal relationship: gynecomastia. Jaundice and increased hepatic enzyme activity (mostly due to cholestasis or hepatitis), in some cases quite severe and requiring hospitalization, have been observed in the post-registration follow-up period while taking amlodipine besylate.

Amlodipine besylate has been used safely in patients with chronic obstructive pulmonary disease, compensated chronic heart failure, coronary artery disease, peripheral artery disease, diabetes mellitus and lipid profile disorders.

Laboratory measures

Losap® AM drug

Some patients showed palpitations after 8 weeks of concomitant administration of amlodipine and losartan, but they were not clinically significant.

In some patients, increased blood creatinine and increased “hepatic” enzyme activity have been observed, but specific laboratory monitoring is not required.

Lozartan

In controlled clinical trials in patients with AH, clinically significant changes in key laboratory parameters were rarely associated with administration of losartan. Hyperkalemia (serum potassium greater than 5.5 mEq/L) was observed in 1.5% of patients. In a clinical study in patients with type 2 diabetes mellitus with proteinuria, hyperkalemia developed in 9.9% of patients taking losartan and in 3.4% of patients taking placebo (see Special Instructions). Elevated alanine aminotransferase (ALT) activity was rarely observed and usually returned to normal after discontinuation of therapy.

Amlodipine

There were no clinically significant changes in standard laboratory parameters associated with amlodipine therapy. No clinically significant changes in serum potassium, serum glucose concentration, triglyceride concentration, total cholesterol, high-density lipoprotein cholesterol, uric acid, blood urea nitrogen or creatinine were observed.

Overdose

Lozap® AM

There are no data on overdose with Lozap® AM. Overdoses with amlodipine and losartan have been described.

Lozartan

There are limited reports of overdose. The most likely manifestation of overdose is a marked decrease in BP and tachycardia; bradycardia may occur due to parasympathetic (vagus) stimulation.

Treatment: symptomatic therapy.

Lozartan and its active metabolite are not excreted by hemodialysis.

Amlodipine

Symptoms: Overdose may lead to excessive peripheral vasodilation with marked BP reduction and possible development of reflex tachycardia. Significant and prolonged systemic hypotensive effect up to and including shock with lethal outcome has been reported.

Treatment: gastric lavage is indicated if necessary. Administration of activated charcoal in healthy volunteers immediately or within 2 hours after oral administration of 10 mg of amlodipine resulted in decrease of its absorption. In case of significant overdose with amlodipine, hemodynamic and respiratory indices should be actively monitored. Frequent measurement of blood pressure is necessary. If arterial hypotension occurs, hemodynamic support, including elevation of the extremities and adequate administration of fluids, should be provided. If arterial hypotension remains resistant to these conservative measures, the administration of vasoconstrictor drugs (e.g., phenylephrine) should be considered, taking into account the RBC and diuresis. Intravenous administration of calcium gluconate is effective in eliminating calcium channel blockade. Since amlodipine is well bound to blood plasma proteins, hemodialysis procedure is ineffective.

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