Lozap AM pills 5mg + 50mg, 30pcs

Composition

1 film coated tablet contains:  

Dosage 5 mg + 50 mg

Active ingredient:

amlodipine camzilate 7.84 mg (based on amlodipine 5.00 mg) and losartan potassium 50.00 mg.

auxiliary substances:

butyl hydroxytoluene 0.10 mg,

sodium carboxymethyl starch 17.00 mg,

microcrystalline cellulose 265.10 mg,

mannitol 40.00 mg,

povidone-KZO 5.00 mg,

crospovidone 12.00 mg,

magnesium stearate 3.00 mg;

shell (hypromellose-2910 8.00 mg, hyprolose 2.00 mg, titanium dioxide 1.80 mg, talc 0.20 mg).

Pharmacological action

The results of two bioequivalence studies involving healthy volunteers showed that Lozap ® AM in doses of 5 mg+50 mg and 5 mg+100 mg is bioequivalent to the combined use of the corresponding doses of amlodipine camzilate and losartan potassium in the form of separate tablets.

Amlodipine

The bioequivalence of amlodipine bezylate and amlodipine camzylate was evaluated in a randomized, blind, cross-sectional comparative study involving healthy volunteers. The results obtained in the study showed that 5 mg amlodipine camzilate tablets are bioequivalent to 5 mg amlodipine bezilate 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): losartan potassium, an angiotensin II receptor antagonist (ARA II), and amlodipine, a slow calcium channel blocker (BMCC). Losartan blocks the vasoconstrictive effect of angiotensin II and its stimulation of aldosterone release by selectively inhibiting the binding of angiotensin II to AT1 receptors in many tissues. Amlodipine is a vasodilator of peripheral arteries, which acts directly on the smooth muscle of blood vessels, which leads to a decrease in peripheral vascular resistance and a decrease in blood pressure.

Losartan

Angiotensin II is a powerful vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and also a crucial pathophysiological link in the development of hypertension. Angiotensin II binds to AT1 receptors found in many tissues (vascular smooth muscle, adrenal glands, kidneys, and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells. AT1 receptors are the second type of receptors that angiotensin II binds to, but its role in regulating cardiovascular function is unknown.

Losartan 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 route of synthesis. Unlike some peptide antagonists of angiotensin II, losartan does not have agonist properties.

Losartan selectively binds to AT1 receptors and does not bind or block the 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 the angiotensin-converting enzyme (ACE, kininase II) responsible for the destruction of bradykinin. Therefore, effects that are 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 effect of losartan.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the 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 at the 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 the transmembrane entry of calcium, affecting vascular smooth muscle cells more than cardiomyocytes.

A negative inotropic effect can be detected in vitro, but in studies on intact animals using amlodipine in therapeutic doses, this effect was not detected. Amlodipine does not affect the serum calcium content. Within the physiological pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by gradual association and dissociation with the receptor binding site, which leads to a gradual development of the effect.

Amlodipine is a vasodilator of peripheral arteries, acting directly on vascular smooth muscle, which leads to a decrease in peripheral vascular resistance and a decrease

in blood pressure.

Lozap ® AM

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

Losartan

Losartan suppresses the increase in systolic and diastolic blood pressure during angiotensin II infusion. At the time of reaching the maximum concentration (Cmax) of losartan in blood plasma 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 losartan use, elimination of the negative feedback consisting in angiotensin II inhibition of renin secretion leads to an increase in plasma renin activity (ARP). An increase in ARP leads to an increase in the concentration of angiotensin II in blood plasma. During 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 blood plasma was observed at the time of reaching the Cmax of losartan. In some patients, an even greater increase in the concentration of angiotensin II was observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, the antihypertensive effect and a decrease in the concentration of aldosterone in blood plasma were manifested after 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin I receptors. After discontinuation of losartan, ARP and angiotensin II concentrations decreased within 3 days to the values observed before starting losartan.

Since losartan is a specific angiotensin II AT1 receptor antagonist, it does not inhibit ACE (kininase II), an enzyme that inactivates bradykinin. A study comparing the effects of losartan at 20 mg and 100 mg doses with those of an ACE inhibitor for the effects 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 the response to angiotensin I and increased the severity of bradykinin-related effects, without affecting the severity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors. The plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing dose. Since losartan and its active metabolite are angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.

In a single 100 mg losartan study that included healthy male volunteers, oral use of losartan on a high-and low-salt diet did not affect glomerular filtration rate (GFR), effective renal plasma flow, or filtration fraction. Losartan had a natriuretic effect, which was more pronounced with a low-salt diet and, apparently, was not associated with suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in uric acid excretion by the kidneys. In patients with hypertension, 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, a significant decrease in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG) was observed. In these patients, losartan stabilized GFR and reduced the filtration fraction.

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

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

In patients with hypertension, losartan at 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 levels.

In general, losartan caused a decrease in the concentration of uric acid in the blood serum (usually less than 0.4 mg / dl), which persisted with long-term treatment.

In controlled clinical trials involving patients with hypertension, there were no cases of drug withdrawal due to an increase in serum creatinine or potassium levels.

A 12-week parallel study, which included patients with left ventricular insufficiency (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 showed positive hemodynamic and neurohormonal effects, which persisted throughout the study. Hemodynamic effects included an increase in cardiac index and a decrease in pulmonary capillary jamming pressure, as well as a decrease in total peripheral vascular resistance, mean systemic blood pressure, and heart rate (HR). The frequency of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in the concentration of aldosterone and norepinephrine in the blood.

Amlodipine

Hemodynamics

In patients with hypertension, after taking therapeutic doses, amlodipine causes vasodilation, which leads to a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by significant changes in heart rate or the concentration of catecholamines in blood plasma with prolonged use. Although a single intravenous injection of amlodipine resulted in a decrease in blood pressure and an increase in heart rate, repeated oral use of amlodipine did not lead to clinically significant changes in heart rate or blood pressure in normotensive patients with exertional angina.

With prolonged oral use once a day, the antihypertensive effect persists for at least 24 hours. The concentration of amlodipine in blood plasma correlates with the antihypertensive effect in both young and elderly patients. The magnitude of the decrease in blood pressure when taking amlodipine also correlates with the severity of the increase in blood pressure before starting treatment. Thus, in patients with moderate hypertension (diastolic pressure 105-114 mm Hg), approximately 50% greater antihypertensive effect was observed than in patients with mild hypertension (diastolic pressure 90-104 mm Hg). In patients with normal blood pressure, there was no clinically significant change in blood pressure (+1/-2 mm Hg).

In patients with hypertension and normal renal function, taking amlodipine in therapeutic doses resulted in a decrease in renal vascular resistance, an increase in GFR and effective renal plasma flow without changing the filtration fraction or proteinuria.

As with other BMCs, hemodynamic parameters of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine generally showed a slight increase in cardiac index without a significant change in the rate of increase in left ventricular pressure at the beginning of the ejection period (dP/dt) or final diastolic pressure or left ventricular volume. In studies evaluating hemodynamic parameters, amlodipine did not have a negative inotropic effect when used in therapeutic doses in healthy volunteers, even when used simultaneously with beta-blockers. However, similar results were observed in healthy volunteers or in patients with compensated heart failure when using drugs that have a 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, intravenous use of 10 mg of amlodipine did not significantly affect the A-H and H-V conductivity and recovery time of the sinus node after pacing. Similar results were obtained in patients taking amlodipine and beta-blockers at the same time. In clinical trials in which patients with hypertension or angina pectoris took amlodipine concomitantly with beta-blockers, there was no undesirable effect on electrocardiographic parameters. In clinical trials involving patients with angina alone, amlodipine therapy did not affect electrocardiographic intervals and did not cause atrioventricular block to a greater extent.

Pharmacokinetics

Suction

Losartan

When taken orally, losartan is well absorbed and undergoes metabolism during the “primary passage” through the liver with the formation of an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan in tablet form is about 33%. The average maximum concentrations of losartan and its active metabolite are reached after 1 h and after 3-4 h, respectively. When losartan was taken during a normal meal, no clinically significant effect on the plasma losartan concentration profile was detected.

Amlodipine

After oral use in therapeutic doses, the plasma cmax of amlodipine is reached in 6-12 hours. The absolute bioavailability of amlodipine is from 64% to 90% of the dose taken. Food intake does not affect the bioavailability of amlodipine.

Distribution

Losartan

Losartan and its active metabolite bind to plasma proteins (mainly albumin) by at least 99%. The volume of distribution of losartan is 34 liters. Studies in rats have shown that losartan practically does not penetrate the blood-brain barrier.

Amlodipine

Studies have shown that in patients with hypertension, approximately 93% of the circulating drug binds to plasma proteins.

Metabolism

Losartan

Approximately 14% of the dose of losartan is converted to its active metabolite by intravenous or oral use. After oral or intravenous use of radiocarbon-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 the patients who participated in the study.

In addition to the active metabolite, biologically inactive metabolites are formed, including two main ones formed as a result of hydroxylation of the butyl side chain, and one minor one – N-2-tetrazole-glucuronide.

Amlodipine

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

Deduction

Losartan

The plasma clearance of losartan and its active metabolite is approximately 600 ml / min and 50 ml / min, respectively. The renal clearance of losartan and its active metabolite is approximately 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 about 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when taking losartan orally at doses up to 200 mg. After oral use, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal half-life of about 2 and 6-9 hours, respectively. When the dosage regimen of the drug is 100 mg once a day, there is no significant accumulation in the blood plasma of either losartan or its active metabolite.

The elimination of losartan and its metabolites is carried out by the kidneys and through the intestines with bile. After oral use of 14C losartan in men, about 35% of radioactivity is detected in the urine and 58% in the feces. After intravenous use of 14C losartan in men, approximately 43% of radioactivity is detected in the urine and 50% in the feces.

Amlodipine

Elimination of amlodipine from the blood plasma occurs in two phases, the final phase of the half-life is about 30-50 hours. Steady-state plasma concentrations of amlodipine are reached after 7-8 days with daily use.

Pharmacokinetics in special patient groups

Lozap ® AM

Lozap ® AM has not been studied in any special patient groups due to the good knowledge of the active ingredients of the drug, losartan and amlodipine. Losartan should be used with caution in patients with impaired renal and hepatic function. It is contraindicated during pregnancy and lactation. No separate studies were conducted with the participation of children and elderly patients.

Amlodipine should be used with caution in patients with impaired liver function. It is contraindicated in the unstable course of cardiovascular diseases, as well as during pregnancy and lactation.

Losartan

Elderly patients

The plasma concentrations of losartan and its active metabolite in elderly male patients with hypertension do not significantly differ from those in young male patients with hypertension.

Gender

The plasma concentrations of losartan in women with hypertension were 2 times higher than the corresponding values in men with hypertension. Concentrations of the active metabolite did not differ between men and women. This clear pharmacokinetic difference, however, is not clinically relevant.

Patients with impaired liver function

When taking losartan orally in patients with mild and moderate alcoholic cirrhosis of the liver, the concentrations of losartan and its active metabolite in blood plasma 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 did not differ from those in patients with unchanged renal function. The area under the concentration-time curve (AUC) of losartan in patients undergoing hemodialysis was approximately 2 times greater than the AUC of losartan in patients with normal renal function. Concentrations of the active metabolite in blood plasma did not change in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite are not eliminated by hemodialysis.

Amlodipine

Patients with impaired renal function

Impaired renal function does not significantly affect the pharmacokinetic parameters of amlodipine, so patients with renal insufficiency can be prescribed the usual initial dose of amlodipine.

Elderly patients and patients with impaired liver function

In elderly patients and patients with hepatic insufficiency, the clearance of amlodipine is reduced, which leads to an increase in AUC by about 40-60%. These patients may require a lower initial dose of amlodipine. A similar increase in AUC was observed in patients with moderate or severe heart failure.

Children and adolescents

Pharmacokinetic studies in patients with hypertension aged 6 to 17 years who took amlodipine at a dose of 1.25 mg to 20 mg showed that the body weight-adjusted clearance and volume of distribution of amlodipine were comparable to those in adult patients.

Indications

Arterial hypertension (patients who are indicated for combination therapy).

Contraindications

Hypersensitivity to any of the components of the drug.

Pregnancy and breast-feeding period.

Age up to 18 years (efficacy and safety of use have not been established).

Concomitant 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 INTERACTION WITH OTHER DRUGS).

Severe hepatic impairment (no experience of use).

Shock (including cardiogenic shock).

Obstruction of the left ventricular outflow tract (for example, severe aortic stenosis).

Hemodynamically unstable heart failure after acute myocardial infarction.

Use in patients with impaired renal function (creatinine clearance less than 20 ml / min) or patients undergoing hemodialysis.

With caution

Bilateral renal artery stenosis or single kidney artery stenosis; hyperkalemia; post-kidney transplant condition (no experience); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with concomitant severe renal impairment; severe heart failure (NYHA Functional Class IV); heart failure with life-threatening arrhythmias; ischemic heart disease; cerebrovascular diseases; primary hyperaldosteronism a history of angioedema; impaired liver function; unstable angina or myocardial infarction.

Patients with reduced circulating blood volume (for example, treated with high doses of diuretics)- symptomatic hypotension may occur.

Side effects

The safety of Lozap® AM was evaluated in 8-week clinical trials involving 646 patients with hypertension, of which 325 patients received amlodipine + losartan combination therapy. During clinical trials, the following adverse events were observed, which were evaluated by researchers as possible, probable or definitely associated with taking the drug (frequent >1% and > > 0.1% From the nervous system Frequent: dizziness, headache. Infrequent: drowsiness. Common disorders Infrequent: weakness, chest discomfort, chest pain, feeling of rapid satiety, peripheral edema. From the gastrointestinal tract Infrequent: abdominal discomfort, dyspepsia, nausea, reflux esophagitis. Skin and subcutaneous tissue disorders Infrequent: pruritus (generalized), urticaria (generalized). From the side of the heart Infrequent: palpitation of the heart. From the side of blood vessels Infrequent: “hot flashes” of blood to the skin of the face, orthostatic hypotension. Respiratory, thoracic and mediastinal disorders Infrequent: shortness of breath. Hearing disorders and labyrinth disorders Infrequent: vertigo. From the side of the kidneys and urinary tract Infrequent: pollakiuria. The following adverse events were observed when using the active ingredients of Lozap® AM in monotherapy. Losartan 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 it cannot reflect the frequency observed in clinical practice. In general, losartan is well tolerated in patients with hypertension. Adverse events are mild and transient and do not require discontinuation of therapy. The overall incidence of adverse events with losartan is comparable to that with placebo. In controlled clinical trials, the frequency of discontinuation due to clinically significant adverse events was 2.3% in the losartan group and 3.7% in the placebo group. In controlled clinical trials of losartan in patients with hypertension, the only treatment-related adverse reaction observed more frequently than with placebo was dizziness, which was observed in the losartan treatment groups with a frequency of 1% or more. In addition, less than 1% of patients experienced dose-dependent orthostatic reactions. Rarely (>0.01% and In double-blind controlled clinical trials in >>1% of patients with hypertension, the following adverse events were observed with losartan (n=2085) or placebo (n=535), regardless of their association with treatment. Common disorders: stomach pain 1.7% (placebo 1.7%); weakness and fatigue 3.8% (3.9%); chest pain 1.1% (2.6%); peripheral edema 1.7% (1.9%). From the cardiovascular system: palpitation 1.0% (placebo 0.4%); tachycardia 1.0% (1.7%). From the digestive system: diarrhea 1.9% (placebo 1.9%); dyspepsia 1.1% (1.5%); nausea 1.8% (2.8%). Musculoskeletal disorders: back pain 1.6% (placebo 1.1%); muscle spasms 1.0% (1.1%). Central nervous system disorders: dizziness 4.1% (placebo 2.4%); headache 14.1% (17.2%); insomnia 1.1% (0.7%). Respiratory disorders: cough 3.1% (placebo 2.6%); nasal edema 1.3% (1.1%); pharyngitis 1.5% (2.6%); sinusitis 1.0% (1.3%); upper respiratory tract infections 6.5% (5.6%). Controlled clinical trials have shown that losartan is generally well tolerated in patients with hypertension and left ventricular hypertrophy. The most common adverse reactions associated with taking losartan were systemic and non-systemic dizziness, asthenia/weakness. In this study, in patients without a history of diabetes mellitus, the incidence of new cases of diabetes mellitus was lower with losartan compared to atenolol (p Since there was no placebo group in this study, it is not known whether this is a positive effect of losartan or an undesirable effect of atenolol. Controlled clinical trials have shown that losartan is generally well tolerated in patients with type 2 diabetes and proteinuria. The most common adverse reactions associated with taking losartan were dizziness, asthenia/weakness, marked decrease in blood pressure and hyperkalemia (see SPECIAL INSTRUCTIONS). The following adverse reactions were observed in clinical practice in the post-marketing period. Hypersensitivity reactions: anaphylactic reactions, angioedema involving the larynx and pharynx causing airway obstruction, and/or angioedema of the face, lips, pharynx, and/or tongue have rarely been observed in patients taking losartan. Some of these patients had a history of angioedema when taking other medications, including ACE inhibitors. Vasculitis, including Schonlein-Henoch purpura, has rarely been reported. From the digestive system: hepatitis (rare), impaired liver function, vomiting. General disorders: a feeling of general discomfort. From the blood system: anemia, thrombocytopenia (rare). Musculoskeletal disorders: myalgia, arthralgia. From the central nervous system: migraine, dysgeusia. From the genitals and breast: erectile dysfunction/impotence. Respiratory system disorders: cough. Skin disorders: urticaria, pruritus, redness of the skin, photosensitization. Since 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 it cannot reflect the frequency observed in clinical practice. The safety of amlodipine bezylate has been evaluated in clinical trials involving more than 11,000 patients. In general, treatment with amlodipine bezilate at a dosage of up to 10 mg once a day was well tolerated.Most of the adverse events observed during amlodipine bezilate therapy were mild to moderate in severity. In controlled clinical trials directly comparing amlodipine bezilate therapy at a dosage of up to 10 mg once a day with placebo, discontinuation of amlodipine bezilate therapy due to adverse events was required only in 1.5% of patients, which does not significantly differ from the placebo group (about 1%). The most frequent (>1%) and the following frequency (% ) of dose-dependent adverse events were observed:: Adverse event 2.5 mg 5.0 mg 10.0 mg Placebo edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Hot flashes 0.7 1.4 2.6 0.0 Palpitation 0.7 1.4 4.5 0.6 Other adverse events that were observed in placebo-controlled clinical trials in more than 1.0% of patients and did not have a clear dose relationship: Adverse event of Amlodipine bezylate (% ) Placebo (%)Headache 7,3 7,8 Fatigue 4,5 2,8 Nausea 2,9 1,9 Abdominal pain 1,6 0,3 Drowsiness 1,4 0,6 Some adverse events, apparently associated with taking amlodipine bezilate and its dose, were more often observed in women than in men: Adverse event of Amlodipine bezylate Placebo Members (% ) Women (% ) Men (% ) Women (%)Oedema 5,6 14,6 1,4 5,1 Hot flashes 1,5 4,5 0,3 0,9 Palpitation 1,4 3,3 0,9 0,9 Drowsiness 1,3 1,6 0,8 0,3 The following adverse events are common (>0,1 From the cardiovascular system: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, marked decrease in blood pressure, peripheral vascular ischemic disorders, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis. From the central and peripheral nervous system: hypesthesia, peripheral neuropathy, paresthesia, tremor, vertigo. From the digestive system: anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gum hyperplasia. Common disorders: allergic reaction, asthenia*, back pain, “hot flashes”of blood to the skin of the face, malaise, pain, rigidity, weight gain, weight loss. Musculoskeletal disorders: arthralgia, osteoarthritis, muscle cramps*, myalgia. Mental disorders: sexual dysfunction (in men* and women), insomnia, increased excitability, depression, unusual dreams, anxiety, depersonalization. Respiratory system disorders: shortness of breath*, nosebleeds. Skin disorders: angioedema, erythema multiforme, pruritus*, skin rash*, erythematous rash, maculopapular rash. From the sensory organs: visual impairment, conjunctivitis, diplopia, eye pain, ringing in the ears. From the urinary system: frequent urination, impaired urination, nocturia. From the autonomic nervous system: dryness of the oral mucosa, increased sweating. From the side of metabolism and nutrition: hyperglycemia, thirst. Hematopoietic disorders: leukopenia, purpura, thrombocytopenia. * These adverse events were observed in less than 1% of placebo-controlled trials, but their frequency was between 1% and 2% in all studies with multiple use of amlodipine. The following adverse events were observed very rarely (Other adverse events were observed sporadically, and it is impossible to establish a causal relationship with medication or concomitant diseases, such as myocardial infarction and angina pectoris. The following adverse events were also observed in the post-marketing follow-up period. Since 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 the drug intake. An undesirable event that was rarely observed in the post-marketing follow-up period without an established causal relationship: gynecomastia. In the post-marketing follow-up period, jaundice and increased activity of “liver” enzymes (mostly due to cholestasis or hepatitis) were observed when taking amlodipine bezilate, in some cases quite severe and requiring hospitalization. Amlodipine bezylate was 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 parameters Lozap ® AM In some patients, a decrease in heart rate was observed after 8 weeks of concomitant use of amlodipine and losartan, but it was not clinically significant. In some patients, an increase in blood creatinine and an increase in the activity of “liver” enzymes was observed, but specific laboratory monitoring is not required. Losartan In controlled clinical trials in patients with hypertension, clinically significant changes in the main laboratory parameters were rarely associated with losartan use. In 1.5% of patients, hyperkalemia was observed (serum potassium is more than 5.5 meq/l). In a clinical study in patients with type 2 diabetes mellitus with proteinuria, hyperkalemia developed in 9.9% of patients taking losartan and 3.4% of patients taking placebo (see Special Instructions). Elevated alanine aminotransferase (ALT) activity was observed in rare cases and usually returned to normal after discontinuation of therapy. Amlodipine There were no clinically significant changes in standard laboratory parameters associated with amlodipine therapy. There were no clinically significant changes in serum potassium, serum glucose, triglyceride concentrations, total cholesterol, high-density lipoprotein cholesterol, uric acid, blood urea nitrogen, or creatinine.

Interaction

Lozap ® AM

No studies of drug interactions of Lozap® AM with other drugs have been conducted. Studies of drug interactions between the active ingredients of Lozap® AM are described below.

Losartan

No clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, or phenobarbital have been identified in clinical studies of pharmacokinetic drug interactions. Rifampicin, being an inducer of drug metabolism, reduces the concentration of the active metabolite of losartan in the blood. In clinical studies, the use of two inhibitors of the P450-4 isoenzyme was studied: ketoconazole and erythromycin. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous use of losartan. Erythromycin did not have a clinically significant effect when taking losartan orally. Fluconazole, an inhibitor of the P450 2C9 isoenzyme, reduced the concentration of the active metabolite of losartan, but the pharmacodynamic significance of concomitant use of losartan and inhibitors of the P450 2C9 isoenzyme has not been studied. It has been shown that patients who do not metabolize losartan to the active metabolite have a very rare and specific defect of the P-2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is carried out by the P4502C9 isoenzyme, and not by the P450A4 isoenzyme.

Concomitant use of losartan, as well as other drugs that block angiotensin II or its effects, with potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium-containing supplements or potassium salts may lead to an increase in serum potassium.

As with other drugs that affect the excretion of lithium, losartan may reduce the excretion of lithium, so when lithium and ARA II preparations are used simultaneously, it is necessary to carefully monitor the concentration of lithium in the blood serum.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of ARA II or ACE inhibitors may be weakened when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (for example, in elderly patients or patients with dehydration, including those taking diuretics), receiving NSAID therapy, including selective COX-2 inhibitors, the simultaneous use of ARA II or ACE inhibitors may cause further deterioration of renal function, including the development of acute renal failure. These effects are usually reversible, so the concomitant use of these drugs should be carried out with caution in patients with impaired renal function.

Dual blockade of the RAAS with ARA II, ACE inhibitors, or aliskiren (a renin inhibitor) is associated with an increased risk of hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal failure) compared to monotherapy. Regular monitoring of blood pressure, renal function, and blood electrolyte levels is necessary in patients taking Lozap® AM and other medications that affect the RAAS at the same time. 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

Data from in vitro studies

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

Cimetidine

Concomitant use of amlodipine and cimetidine does not affect the pharmacokinetics of amlodipine.

Grapefruit juice

Concomitant use of 240 ml of grapefruit juice with a single oral dose of 10 mg of amlodipine in healthy volunteers did not significantly affect the pharmacokinetics of amlodipine.

Antacids containing magnesium or aluminum hydroxide

Concomitant use of an antacid containing magnesium or aluminum hydroxide with a single dose of amlodipine did not significantly affect the pharmacokinetics of amlodipine.

Sildenafil 

A single 100 mg dose of sildenafil in patients with hypertension did not affect the pharmacokinetics of amlodipine. When taking amlodipine simultaneously with sildenafil, each of the drugs independently exerted its own antihypertensive effect.

Atorvastatin

Simultaneous multiple use of amlodipine at a dose of 10 mg with atorvastatin at a dose of 80 mg did not lead to significant changes in the steady-state pharmacokinetic parameters of atorvastatin.

Simvastatic diseases

Simultaneous multiple use of amlodipine 10 mg with simvastatin 80 mg resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. The dose of simvastatin when used concomitantly with amlodipine should not exceed 20 mg once a day.

Digoxin

Concomitant use of amlodipine and digoxin did not result in changes in blood digoxin concentrations or renal digoxin clearance in healthy volunteers.

Ethanol (alcohol) 

Single and repeated use of amlodipine at a dose of 10 mg did not significantly affect the pharmacokinetics of ethanol.

Warfarin

Concomitant use of amlodipine and warfarin does not affect the increase in prothrombin time in response to warfarin.

Inhibitors of the CYP3A4 isoenzyme

In elderly patients with hypertension, the concomitant use of diltiazem at a daily dose of 180 mg and amlodipine at a dose of 5 mg resulted in a 1.6-fold increase in the AUC of amlodipine. In healthy volunteers, concomitant use of erythromycin and amlodipine does not significantly affect the AUC of amlodipine, but strong inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole, ritonavir) can significantly increase the concentration of amlodipine in blood plasma. Symptoms of hypotension and edema should be monitored regularly when amlodipine is co-administered with CYP3A4 inhibitors.

Inducers of the CYP3A4 isoenzyme

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

How to take, course of use and dosage

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

It is recommended to drink the drug with a sufficient amount of water.

Lozap ® AM can be taken in combination with other antihypertensive agents. Patients who do not achieve adequate blood pressure control when using losartan or amlodipine alone may switch to combination therapy with the drug 

Lozap® AM.

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

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

Lozap ® AM 5 mg+50 mg is prescribed to patients who have not achieved adequate blood pressure control when using amlodipine 5 mg or losartan 50 mg in monotherapy.

Lozap AM 5 mg+100 mg is prescribed to patients who have not achieved adequate blood pressure control with losartan 100 mg or Lozap AM 5 mg+50 mg.

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

Use in patients with impaired renal function

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

If the use of Lozap ® AM is therapeutically necessary in patients with reduced circulating blood volume( BCC), patients with impaired liver function, or elderly patients, individual dose selection of active substances (i. e., amlodipine and losartan) should be carried out prior to the use of the combined drug with fixed doses of active substances.

Use in patients with reduced BCC

In patients with reduced BCC (for example, those treated with high doses of diuretics), the recommended starting dose of losartan is 25 mg once a day (see SPECIAL INSTRUCTIONS). Since Lozap ® AM does not have a dosage containing losartan 25 mg, this dose should be administered in monotherapy with losartan.

Use in patients with impaired liver function

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

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

Use in elderly patients

In elderly patients, due to reduced clearance, amlodipine therapy is usually recommended to start with a dose of 2.5 mg once a day. Since Lozap ® AM does not have a dosage containing 2.5 mg of amlodipine, this dose should be administered in monotherapy with amlodipine.

Use in children and adolescents

Since the efficacy and safety of Lozap® AM in patients under 18 years of age have not been studied, the use of Lozap® AM in this group of patients is contraindicated.

Overdose

Lozap ® AM

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

Losartan

Information about overdose is limited. The most likely manifestation of overdose is a marked decrease in blood pressure and tachycardia; bradycardia may occur due to parasympathetic (vagal) stimulation.

Treatment: symptomatic therapy.

Losartan and its active metabolite are not eliminated by hemodialysis.

Amlodipine

Symptoms: overdose can lead to excessive peripheral vasodilation with a marked decrease in blood pressure and the possible development of reflex tachycardia. Severe and prolonged systemic hypotensive effects have been reported, up to fatal shock.

Treatment: gastric lavage is indicated if necessary. The use of activated carbon in healthy volunteers directly or within 2 hours after ingestion of 10 mg of amlodipine led to a decrease in the absorption of the latter. In case of significant overdose with amlodipine, it is necessary to actively monitor hemodynamic and respiratory parameters. Frequent blood pressure measurement is necessary.

If arterial hypotension occurs, hemodynamic support should be provided, including elevated position of the limbs and adequate use of fluids. If hypotension remains resistant to these conservative measures, the use of vasoconstrictor drugs (for example, phenylephrine) should be considered, taking into account BCC and diuresis. Intravenous use of calcium gluconate is effective to eliminate calcium channel blockage. Since amlodipine binds well to plasma proteins, hemodialysis is ineffective.

Special instructions

Lozap ® AM

Arterial hypotension

Patients with reduced BCC (for example, those treated with high doses of diuretics) or with severe aortic stenosis may experience symptomatic hypotension. Correction of such conditions should be carried out before prescribing Lozap ® AM or starting treatment with a lower dose of Lozap® AM (see Dosage and use). Acute arterial hypotension is unlikely due to the gradual onset of the drug’s action.

Impaired liver function

Based on pharmacokinetic data that have shown a significant increase in the concentration of losartan in blood plasma in patients with cirrhosis of the liver, patients with a history of impaired liver function should be prescribed lower doses of losartan (see Pharmacological properties, Pharmacokinetics; Method of use and doses).

Since amlodipine is mainly metabolized in the liver and the elimination half-life in patients with impaired liver function is 56 hours, when prescribing amlodipine to patients with severe hepatic insufficiency, titration of the dose should be carried out gradually.

Losartan

Hypersensitivity reactions

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 (see Side effect).

Embryotoxicity

The use of drugs that affect the RAAS in the second and third trimester of pregnancy reduces fetal kidney function and increases the morbidity and mortality of the fetus and newborn. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities.Possible adverse events in newborns include cranial hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is diagnosed, Lozap® AM should be discontinued immediately (see Use during pregnancy and lactation).

Violation of the water-electrolyte balance

Impaired water-electrolyte balance is characteristic of patients with impaired renal function with or without diabetes mellitus, so careful monitoring of these patients is necessary. In clinical trials involving patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was higher in the losartan group than in the placebo group. Several patients discontinued therapy due to hyperkalemia (see SIDE EFFECTS, Laboratory parameters).

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

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

Like all drugs with vasodilating effects, ARA II should be administered with caution in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Coronary heart disease and cerebrovascular diseases

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

Chronic heart failure (CHF) 

As with other medications that affect the RAAS, patients with CHF and with or without impaired renal function are at risk of developing severe 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 to patients in these groups.

Primary hyperaldosteronism

Since patients with primary hyperaldosteronism generally do not respond positively to antihypertensive agents that act by inhibiting RAAS, losartan is not recommended in this group of patients.

Impaired liver function

Data from pharmacokinetic studies indicate that the concentration of losartan in the blood plasma in patients with cirrhosis of the liver is significantly increased, so patients with a history of liver disease should be prescribed losartan at a lower dose. There is no experience of using losartan in patients with severe hepatic impairment, so the drug should not be used in patients of this group (see Pharmacological properties, Pharmacokinetics; Contraindications; Method of use and doses).

Impaired renal function

Due to RAAS inhibition, some predisposed patients experienced changes in renal function, including the development of renal failure.

These changes may occur after discontinuation of treatment.

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

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

Amlodipine

Unstable angina and myocardial infarction

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

Special patient groups

Children and teenagers

The efficacy and safety of Lozap® AM in children and adolescents under 18 years of age have not been established.

If newborns whose mothers took Lozap® AM during pregnancy develop oliguria or hypotension, 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 kidney function.

Elderly patients

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

In elderly patients, due to reduced clearance resulting in an increase in amlodipine AUC by approximately 40-60%, amlodipine therapy is usually recommended to start with a dose of 2.5 mg once a day. Since Lozap ® AM does not have a dosage containing 2.5 mg of amlodipine, this dose should be administered in monotherapy with amlodipine.

Influence on the ability to drive vehicles and mechanisms

No studies have been conducted to assess the effect on the ability to drive vehicles and work with mechanisms, however, some undesirable effects observed with the use of Lozap® AM may affect the ability to drive vehicles and work with mechanisms (see Side effect).

Form of production

Film-coated tablets 5 mg+50 mg.

Storage conditions

Store at a temperature not exceeding 30°C.

Keep out of the reach of children.

Shelf

life is 2 years.

Active ingredient

Amlodipine, Losartan

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension