Lortense (Lortenza)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmlodipine + LosartanAmlodipine + Losartan
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    MSD FARMASYUTIKALS, LLC     Russia
  • Lortense
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    KRKA-RUS, LLC     Russia
    • Dosage form: & nbspfilm coated tablets
    Composition:

    Composition

    1 tablet 5 mg + 50 mg

    Core

    Active substances:

    Amlodipine besylate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg, Losartan A substance - granules 163.55 mg, contains potassium losartan 50.00 mg

    Excipients: cellactose 801 36.45 mg, microcrystalline cellulose 212.96 mg, pregelatinized starch 54.00 mg, sodium carboxymethyl starch - 22,00 mg, ferric iron oxide yellow (E172) 0.40 mg, silicon dioxide colloid 1.60 mg, magnesium stearate 5.10 mg

    Film Sheath:

    Foam II white2 25.71 mg, ferric iron oxide yellow (E172) 1.03 mg, ferric iron oxide red (E172) 0.26 mg

    on 1 tablet of 10 mg + 50 mg Core

    Active substances:

    Amlodipine besylate (amlodipine besylate) 13.88 mg, equivalent to amlodipine 10.00 mg, Losartan A substance - granules 163.55 mg, contains potassium losartan 50.00 mg

    Excipients: cellactose 801 36.45 mg, microcrystalline cellulose 206.02 mg, pregelatinized starch 54.00 mg, sodium carboxymethyl starch - 22,00 mg, ferric iron oxide yellow (E172) 0.40 mg, silicon dioxide colloid 1.60 mg, magnesium stearate 5.10 mg

    Film sheath:

    Opaprai II white "24.40 mg, ferric iron oxide red (E172) 2.60 mg

    1 tablet 5 mg + 100 mg

    Core

    Active substances:

    Amlodipine besylate (amlodipine besylate) 6.94 mg, equivalent to amlodipine 5.00 mg, Losartan A substance - granules 327.10 mg, contains potassium losartan 100.00 mg

    Excipients: cellactose 801 72.90 mg, microcrystalline cellulose 212.96 mg, pregelatinized starch 54.00 mg, sodium carboxymethyl starch - 22,00 mg, iron dye oxide yellow (E172) 0.40 mg, silicon dioxide colloidal - 2,10 mg, magnesium stearate 6.60 mg

    Film Sheath:

    Opadrai II white 29.75 mg, iron dye red oxide (E172) 0.25 mg

    on 1 tablet of 10 mg + 100 mg

    Core

    Active substances:

    Amlodipine besylate (amlodipine besylate) 13.88 mg, equivalent to amlodipine 10.00 mg, Losartan A substance - granules 327.10 mg, contains potassium losartan 100.00 mg

    Excipients: cellactose 801 72.90 mg, microcrystalline cellulose 206.02 mg, pregelatinized starch 54.00 mg, sodium carboxymethyl starch - 22,00 mg, iron dye oxide yellow (E172) 0.40 mg, silicon dioxide colloidal - 2,10 mg, magnesium stearate 6.60 mg

    Film Sheath:

    Opadrai II white 29.00 mg, ferric iron oxide yellow (E172) 1.00 mg

    1 Zellactose 80: lactose monohydrate (75%), cellulose (25%).

    2 Opaprai II white: polyvinyl alcohol (40.0%), titanium dioxide (E171) (25.0%), macrogol (20.2%), talc (14.8%).

    Description:

    Tablets 5 mg + 50 mg:

    Oval, slightly biconvex tablets, covered with a film coat of light brown with an orange tint of color.

    Tablets 10 mg + 50 mg:

    Oval, slightly biconvex tablets, covered with a film shell of a red-brown color.

    Tablets 5 mg + 100 mg:

    Oval, biconvex tablets, covered with a film shell of pink color.

    Tablets 10 mg + 100 mg:

    Oval, biconvex tablets covered with a film coat of pale brownish-yellow color.

    Type of tablets at the break for all dosages: a rough mass consisting of two layers - white or almost white and light yellow in color.

    Pharmacotherapeutic group:antihypertensive agent combined (blocker of "slow" calcium channels + angiotensin II receptor antagonist)
    ATX: & nbsp

    C.08.C.A.01   Amlodipine

    C.09.C.A.01   Losartan

    Pharmacodynamics:

    The drug Lortens is a combination of two active components with complementary antihypertensive action: amlodipine (blocker "slow" calcium channel (BCC)) and losartan (an angiotensin II receptor antagonist (APA II)).Active components of the drug have a different mechanism of antihypertensive action: amlodipine causes vasodilation, reducing the overall peripheral vascular resistance (OPSS), losartan, affects the renin-angiotensin-aldosterone system (RAAS) (inhibits the effects of angiotensin II), which leads to a more pronounced decrease in blood pressure (BP) compared to that of monotherapy with each drug.

    Amlodipine

    Amlodipine - a derivative of dihydropyridine, blocks "slow" calcium channels and reduces the transmembrane current of calcium ions in cardiomyocytes and smooth muscle cells of blood vessels. The antihypertensive effect of amlodipine is associated with a direct relaxing effect on the smooth muscles of arterial vessels. In preclinical studies amlodipine had a more pronounced effect on the smooth muscle cells of the blood vessels compared with cardiomyocytes. Amlodipine does not adversely affect either the atrioventricular conduction, nor the contractility of the myocardium. It reduces the resistance of the kidney vessels and increases the renal blood flow. Studies of amlodipine in patients with chronic heart failure (XCH) II-IV functional class by classification NYHA (classification of the New York Heart Association) showed that amlodipine does not adversely affect exercise tolerance, a fraction of the release or concentration of lipids and glucose in the blood plasma. After a single admission of amlodipine, the action begins within 2-4 hours and persists for 24 hours. The maximum antihypertensive effect is achieved no earlier than 4 weeks after the start of therapy. Amlodipine reduces blood pressure in patients who are in the "lying" and "sitting", as well as with physical activity. Thanks to the gradual development of the pharmacodynamic effect amlodipine does not cause a sharp decrease in blood pressure or reflex tachycardia. Amlodipine reduces the severity of left ventricular hypertrophy. Hemodynamic effects remain unchanged with long-term use of amlodipine.

    Losartan

    Losartan is a synthetic APA II (type AT1) for oral administration. Angiotensin II is a potent vasoconstrictor, the main active hormone of RAAS and an important defining pathophysiological link in the development of hypertension (AH).Angiotensin II binds to AT1receptors found in many tissues (smooth muscle tissue of the vessels, adrenal glands, kidneys and heart) and performs important biological functions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of vascular smooth muscle cells. Losartan selectively blocks AT1-receptors. Losartan and its pharmacologically active carboxylated metabolite (E-3174) both under conditions in vitro, both in the in vivo block all the physiological effects of angiotensin II, regardless of the source or route of its synthesis.

    Losartan does not possess the properties of an agonist and does not block the receptors of other hormones or ion channels involved in the regulation of cardiovascular activity. Losartan does not inhibit angiotensin-converting enzyme (ACE), which destroys bradykinin. Accordingly, does not cause an increase in the incidence of adverse effects mediated by bradykinin.

    Suppression of regulation of renin secretion under the action of angiotensin II by the mechanism of "negative" feedback in the treatment of losartan causes an increase in plasma renin activity (ARP), which leads to an increase in the concentration of angiotensin II in the blood plasma.However, the antihypertensive effect and a decrease in plasma aldosterone concentration persist, indicating an effective blockade AT1receptors. After discontinuation of losartan, ARP blood and angiotensin II concentration in the blood plasma decrease within 3 days to the initial values.

    Pharmacokinetics:

    Amlodipine

    Suction

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

    Distribution

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

    Metabolism

    Amlodipine undergoes a slow but active metabolism in the liver in the absence of a significant "primary transmission" effect. Metabolites do not have significant pharmacological activity.

    Excretion

    The final half-life (T1/2) from the blood plasma is 30-40 hours. Plasma clearance is 7 ml / min / kg.Approximately 60% of metabolites and 10% of amlodipine are unchanged in the form of kidneys, 20-25% through the intestine.

    Pharmacokinetics of special groups of patients

    Patients with impaired hepatic function

    The experience with amlodipine in patients with impaired liver function is limited. Have patients with impaired hepatic function there is an increase in T1/2.

    Losartan

    Suction

    After oral administration losartan well absorbed. Systemic bioavailability of losartan for oral administration is approximately 33%. FROMmOh losartan and its active metabolite in blood plasma are reached after 1 hour and after 3-4 hours, respectively.

    Distribution

    Lozartan and its active metabolite bind to 99% of plasma proteins (mainly albumin). Vd losartan is 34 liters.

    Metabolism

    Losartan is metabolized by "primary passage" through the liver to form an active carboxylated metabolite (E-3174) and other inactive metabolites.

    Approximately 14% of the dose of losartan administered intravenously or ingested is converted to its active metabolite. After ingestion or intravenous administration of radioactive carbon labeled potassium losartan (14FROM losartan), most of the radioactive label in the bloodstream corresponded to losartan and its active metabolite. The minimum level of biotransformation of losartan in its active metabolite was observed in approximately 1% of patients participating in clinical studies.

    Excretion

    The plasma clearance of losartan and its active metabolite is 600 ml / min and 50 ml / min, respectively. The renal clearance of losartan and its active metabolite is 74 ml / min and 26 ml / min, respectively. When taking losartan, about 4% of the dose is excreted by the kidneys unchanged and 6% of the dose is excreted by the kidneys as an active metabolite. The pharmacokinetics of losartan and its active metabolite is linear when administered in doses up to 200 mg.

    When administered, the concentration of losartan and its active metabolite in the blood plasma decreases polyexponentially with a finite T1 / 2 about 2 hours and 6-9 hours, respectively. In a dose of 100 mg taken once a day, neither losartan, nor its active metabolite is not cumulated in blood plasma. Losartan and its metabolites are excreted by the kidneys and through the intestines with bile. Ingestion and intravenous administration 14With losartan in humans, about 35% and 43% of the radioactivity, respectively, of losartan and its active metabolite was excreted by the kidneys and 58% and 50%, respectively, through the intestines.

    Pharmacokinetics of special groups of patients

    Elderly patients

    The concentrations of losartan and its active metabolite in blood plasma in elderly patients with hypertension do not differ significantly from these indices in young patients with AH.

    Floor

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

    Patients with impaired hepatic function

    In patients with mild and moderate alcoholic cirrhosis of the liver, the concentration of losartan and its active metabolite in blood plasma increased by 5 and 1.7 times, respectively, in comparison with similar indices in young healthy male volunteers when losartan was administered.

    Patients with impaired renal function

    The concentration of losartan in the blood plasma does not change in patients with creatinine clearance (CC) greater than 10 ml / min. Area under the curve "concentration-time" (AUC) losartan in patients on hemodialysis was approximately 2 times higher than in AUC losartan in patients with normal renal function. The concentrations of the active metabolite in plasma did not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite are not excreted by hemodialysis.

    Indications:

    - Hypertension (patients, which shows a combination therapy with amlodipine and losartan).

    Contraindications:

    - Hypersensitivity to active active ingredients and / or auxiliary components of the drug.

    - Pregnancy and lactation (see. Section "Pregnancy and lactation")

    - Severe hepatic failure (more than 9 on the Child-Pugh scale).

    - Haemodynamically expressed stenosis of the aortic aorta.

    - Hemodynamically unstable heart failure after acute myocardial infarction.

    - Shock (including cardiogenic shock).

    - Age to 18 years (effectiveness and safety not established).

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

    - Severe renal dysfunction (KK less than 20 ml / min), use in patients on hemodialysis.

    - Simultaneous use with aliskiren in patients with diabetes mellitus or renal dysfunction (CC less than 60 ml / min).

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

    Carefully:bilateral stenosis of the renal arteries or stenosis of the single kidney, condition after kidney transplantation (no experience of use), coronary heart disease, heart failure with life-threatening arrhythmias, cerebrovascular disease, primary hyperaldosteronism, history of angioedema, unstable angina, use in patients with low volume of circulating blood (BCC) (for example, when using high doses of diuretics, severe diarrhea, vomiting and other conditions leading to hypovole s), in patients who are on a diet with restriction of salt, hyperkalemia, hypotension, liver failure (less than 9 points on a scale Child-Pugh), sick sinus syndrome (bradycardia, tachycardia), heart failure nonischemic etiology (II-IV functional class by classification NYHA), aortic and / or mitral stenosis, hypertrophic obstructive cardiomyopathy (GOKMP), acute myocardial infarction (and within 1 month after infarction), use in elderly patients.
    Pregnancy and lactation:

    Pregnancy

    The use of Lortense during pregnancy is contraindicated, at the onset of pregnancy should immediately stop taking the drug.

    Medicines (drugs) that affect RAAS can cause damage and death of the fetus and newborn in pregnant women. Single cases of the use of ACE inhibitors in pregnancy are described.

    The use of drugs directly affecting the RAAS in the 2nd and 3rd trimesters of pregnancy is associated with fetal damage and complications in newborns such as hypotension, neonatal hypoplasia of the skull bones, anuria, reversible and irreversible renal failure. There were also cases of oligohydramnion, presumably developed as a result of decreased kidney function in the fetus. In these cases, oligohydramnios was associated with limb contractures, craniofacial deformities and fetal lung hypoplasia.In addition, there were cases of premature birth, intrauterine growth retardation and arterial duct prolapse, but no association with APA II was found in these cases. The listed side effects, apparently, are not a consequence of the use of ARA II in the first trimester of pregnancy. Pregnant women taking ARA II preparations in the first trimester of pregnancy should be necessarily informed about the consequences of taking ARA II in the II and III trimesters of pregnancy.

    Depending on the period of pregnancy, a stress test, a non-stress test or a determination of the biophysical profile of the fetus can be used to assess the functional state of the fetus. Patients and the physician should be aware that the oligohydramnion develops with irreversible damage to the fetus. Newborns, whose mothers took during the pregnancy of ARA II, should be under medical supervision, taking into account the risk of developing arterial hypotension, oliguria and hyperkalemia. With the development of oliguria, in the first place, correction of blood pressure and renal perfusion is necessary. Exchange hemotransfusion or hemodialysis is necessary to correct arterial hypotension and / or to replace kidney function.

    Amlodipine

    The safety of the use of amlodipine in pregnancy is not established. In animal experiments, signs of reproductive toxicity were observed with high doses of amlodipine. The use of amlodipine during pregnancy is possible in the absence of safe hypotensive alternative therapy, and if the potential benefit to the mother exceeds the possible risk to the fetus.

    Losartan

    The use of drugs in the II and III trimesters of drugs that are active in RAAS can cause serious damage or even fetal death, so when planning pregnancy or when it occurs, stop taking losartan and, if necessary, transfer to alternative antihypertensive therapy with a safety profile. Renal perfusion in the fetus, depending on RAAS, develops from the second trimester of pregnancy, so the risk to the fetus increases with the use of losartan in the II and III trimesters of pregnancy.

    Breastfeeding period

    Whether amlodipine and / or losartan is isolated in breast milk, preclinical studies in animals show significant concentrations of amlodipine and / or the active metabolite of losartan in breast milk.

    The use of Lortense is contraindicated in the period of breastfeeding.

    Fertility

    Amlodipine

    In some patients with the use of calcium channel blockers, reversible biochemical changes in the sperm head were noted. Clinical evidence of the potential impact of amlodipine on fertility is not enough. It was reported that a study on rats revealed a side effect on the fertility of male rats.

    Losartan

    In studies in vitro and in vivo mutagenic properties of losartan were not detected. Fertility and reproductive function of male rats receiving oral doses up to 150 mg / kg / day did not change. When a dose of 100 mg / kg / day or more was administered to female rats, a decrease in the number of yellow bodies, implants, and embryos was observed.

    Dosing and Administration:

    Inside, 1 time per day, regardless of the time of eating, squeezed a small amount of water.

    The recommended dose of Lortense is 1 tablet per day.

    The Lortens preparation at a dose of 5 mg + 50 mg is prescribed for patients who did not achieve adequate BP control when using amlodipine in a dose of 5 mg or losartan at a dose of 50 mg in monotherapy.

    The drug Lortensa at a dose of 5 mg + 100 mg is prescribed for patients who did not achieve adequate control of blood pressure when using losartan in a dose of 100 mg or Lortense in a dose of 5 mg + 50 mg.

    The drug Lortensa in a dose of 10 mg + 50 mg is prescribed for patients who did not achieve adequate BP control when using amlodipine at a dose of 10 mg or Lortense in a dose of 5 mg + 50 mg.

    The drug Lortensa in a dose of 10 mg + 100 mg is prescribed for patients who did not achieve adequate control of blood pressure when using Lortense in a dose of 5 mg + 100 mg or 10 mg + 50 mg.

    The dose is selected after previous titration of the doses of individual components of the drug. If a change in the dose of one of the active substances in a fixed combination preparation is required (for example, due to a newly diagnosed disease, a change in the patient's condition or drug interaction), individual doses of individual components need to be individually selected. The maximum daily dose is 10 mg + 100 mg.

    Patients simultaneously taking losartan and amlodipinecan be transferred to a Lortense preparation containing losartan and amlodipine in the same doses.

    Impaired renal function

    With KK from 50 to 20 ml / min dose adjustment is not required.

    The drug Lortens is contraindicated in patients with CC less than 20 ml / min and patients on hemodialysis (see the section "Contraindications"),

    Patients with reduced BCC

    In patients with reduced BCC (eg, due to treatment with high doses of diuretics, etc.), the initial dose of losartan should be reduced to 25 mg once daily. Due to the lack of a dosage containing 25 mg of losartan in Lortens, the dose should be given in monotherapy with losartan.

    Before using Lortens, it is necessary to restore BCC and sodium content in blood plasma.

    Impaired liver function

    Patients with impaired function (less than 9 on the Child-Pugh scale) in a history of lower doses of losartan are recommended. Due to the lack of a dosage containing 25 mg of losartan in Lortens, the dose should be given in monotherapy with losartan.

    Use of the drug Lortenza possible in patients with impaired liver function (less than 9 points on the Child-Pugh), on which the doctor to recommend the use of losartan 50mg.

    Elderly patients

    In elderly patients, correction of the dose of Lortense is not required, but the dose should be increased cautiously.

    Children and teens

    Lortense should not be given to children and adolescents under 18 years of age, as there is no data on the efficacy and safety of use in this group of patients.

    Side effects:

    Frequency classification development of side effects of the World Health Organization (WHO):

    Often > 1/10

    Frequently from> 1/100 to <1/10

    Infrequently from> 1/1000 to <1/100

    Rarely from> 1/10000 to <1/1000

    Very rarely <1/10000

    Frequency unknown - can not be estimated from the available data.

    MedDRA

    Undesirable effects

    Frequency of development

    Amlodipine

    Losartan

    Infectious and parasitic

    Urinary tract infection

    -

    Frequency

    unknown

    diseases




    Violations of the blood and lymphatic system

    Leukopenia

    Rarely

    _


    Thrombocytopenia

    Rarely

    Frequency

    unknown


    Anemia

    -

    Frequency

    unknown

    Immune system disorders

    Anaphylactic reactions

    _

    Rarely


    Angioedema *

    Rarely

    Rarely


    Vasculitis, including hemorrhagic vasculitis (purple Shenlaine-Genocha)


    Rarely


    Hypersensitivity reactions

    Rarely

    Rarely

    Disorders from the metabolism and nutrition

    Hyperglycaemia

    Rarely

    -

    Disorders of the psyche

    Insomnia, mood lability (including anxiety)

    Infrequently

    -


    Depression

    Infrequently

    Frequency

    unknown


    Confusion of consciousness

    Rarely

    _

    Disturbances from the nervous system

    Dizziness

    Often

    Often


    Drowsiness

    Often

    Infrequently


    Headache

    Often

    Infrequently


    Sleep disorders

    _

    Infrequently


    Paresthesia

    Infrequently

    _


    Hypesesia

    Infrequently

    _


    Tremor

    Infrequently

    _


    Dysgeusia

    Infrequently

    Frequency

    unknown


    Muscular hypertonia, peripheral neuropathy

    Rarely

    -


    Migraine

    -

    Frequency

    unknown

    Disturbances on the part of the organ of sight

    Visual impairment (including diplopia)

    Infrequently

    -

    Hearing disorders and labyrinthine disorders

    Vertigo

    _

    Often


    Noise in ears

    Infrequently

    Frequency

    unknown

    Infringements from

    Heart palpitations

    Often

    1 Infrequently

    hearts

    Angina pectoris

    -

    Infrequently


    Myocardial infarction, arrhythmia (bradycardia, ventricular tachycardia, atrial fibrillation)

    Rarely


    Vascular disorders

    Feeling of "tidal" blood to the skin of the face

    Often

    -


    Orthostatic hypotension (including dose-dependent orthostatic reactions) **


    Infrequently


    Marked decrease in blood pressure

    Infrequently



    Vasculitis

    Rarely


    Disturbances from the respiratory system, chest and mediastinal organs

    Dyspnea

    Infrequently

    _


    Rhinitis

    Infrequently

    _


    Cough

    Rarely

    Frequency

    unknown

    Infringements from

    digestive

    systems

    Abdominal pain

    Often

    Infrequently


    Nausea

    Often

    _


    Vomiting, indigestion, a change in the bowel movement (including diarrhea and constipation), dryness of the oral mucosa

    Infrequently



    Thirst

    Infrequently

    _


    Constipation

    _

    Infrequently


    Gastritis, gingival hyperplasia

    Rarely

    _


    Pancreatitis

    Rarely

    Frequency

    unknown


    Diarrhea

    -

    Frequency

    unknown

    Disturbances from the liver and bile ducts

    Hepatitis

    Rarely

    Rarely


    Impaired liver function

    -

    Frequency

    unknown


    Jaundice

    Rarely

    _


    Increased activity of "liver enzymes"

    Rarely

    -

    Disturbances from the skin and subcutaneous tissues

    Skin rash

    Infrequently

    Infrequently


    Alopecia, purpura, discoloration, increased

    sweating, exanthema

    Infrequently



    Itchy skin

    Infrequently

    Frequency

    unknown


    Hives

    Rarely

    Frequency

    unknown


    Photosensitivity

    Rarely

    Frequency

    unknown


    Multiforme exudative erythema, exfoliative dermatitis, Stevens-Johnson syndrome

    Rarely


    Disturbances from musculoskeletal and connective tissue

    Swelling of the ankles

    Often

    _


    Muscle cramps

    Infrequently

    _


    Myalgia

    Infrequently

    Frequency

    unknown


    Arthralgia

    Infrequently

    Frequency

    unknown


    Rhabdomyolysis

    -

    Frequency

    unknown


    Backache

    -

    Frequency

    unknown

    Disorders from the kidneys and urinary tract

    Painful urge to urinate, nocturia, frequent urination

    Infrequently

    -

    Violations of the genitals and mammary gland

    Erectile

    dysfunction / impotence

    Infrequently

    Frequency

    unknown


    Gynecomastia

    Infrequently

    _

    General disorders and disorders at the site of administration

    Increased fatigue

    Often

    Infrequently


    Peripheral edema

    Often

    Infrequently


    Asthenia

    Infrequently

    Infrequently


    Malaise

    Infrequently

    Frequency

    unknown


    Pain

    Infrequently

    _


    Flu-like symptoms

    -

    Frequency

    unknown

    Laboratory and

    Hyperkalemia

    -

    Often


    Increased activity

    alanine aminotransferase

    (ALT) ***

    -

    Rarely

    Hyponatremia

    -

    Frequency

    unknown

    Weight gain, weight loss

    Infrequently

    -

    * Including edema of the larynx, vocal cords, face, lips, pharynx and / or tongue (with the development of airway obstruction), some patients had an angioedema with a history of treatment with other drugs, including ACE inhibitors.

    ** Especially in patients with reduced BCC (for example, in patients with severe heart failure or after treatment with high doses of diuretics).

    *** Usually passes after drug discontinuation.

    Overdose:

    Cases of overdose with a fixed combination of amlodipine / losartan are unknown. Below are the data on the overdose of amlodipine and losartan, taken separately.

    Amlodipine

    Symptoms: marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including with the development of shock and death).

    Treatment: reception of activated carbon (the use of activated carbon in healthy volunteers immediately or within 2 hours after ingestion of 10 mg of amlodipine led to a significant decrease in its absorption). If necessary, gastric lavage is indicated. Clinically significant arterial hypotension with an overdose of amlodipine requires a set of measures to normalize the state of the cardiovascular system, it is necessary to give an elevated position of the lower extremities, to carry out constant monitoring of the functional parameters of the heart and respiratory system, bcc and diuresis. Intensive symptomatic therapy.To restore the vascular tone and blood pressure, vasoconstrictive drugs are used (in the absence of contraindications to their use), with the goal of eliminating the calcium channel blockade - intravenous calcium gluconate. Hemodialysis is ineffective.

    Losartan

    There are limited data on the overdose of losartan.

    Symptoms: marked decrease in blood pressure, tachycardia; bradycardia due to parasympathetic (vagal) stimulation.

    Treatment: with the development of symptomatic arterial hypotension, supportive therapy is conducted. Hemodialysis for losartan and its active metabolite is ineffective.

    Interaction:

    The antihypertensive effect of Lortense may increase with simultaneous use with other antihypertensive drugs. Therefore, the simultaneous use of various antihypertensive drugs should be justified.

    Amlodipine

    The simultaneous use of amlodipine with thiazide diuretics, alpha-blockers or ACE inhibitors is considered safe.

    Unlike other BCCC, clinically significant interaction of amlodipine (III generation of BCCI) was not detected with concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin.It is possible to enhance the antihypertensive effect of BCCK when used simultaneously with thiazide and loop diuretics, ACE inhibitors and nitrates, and also with simultaneous use with alpha 1-blockers, neuroleptics. Simultaneous use of amlodipine with isozyme inhibitors CYP3A4 requires careful monitoring of symptoms of arterial hypotension and peripheral edema. With the simultaneous use of diltiazem in a dose of 180 mg per day and amlodipine at a dose of 5 mg per day in elderly patients, the system exposure of amlodipine increases by 60%. Erythromycin with simultaneous application increases CmOh Amlodipine in blood plasma in young patients by 22%, and in elderly patients - by 50%. At the same time, strong inhibitors of isoenzyme CYP3A4 (ketoconazole, itraconazole, ritonavir) can increase the concentration of amlodipine in the blood plasma to an even greater extent.

    Despite the fact that an accurate quantitative evaluation of the interaction of amlodipine and isoenzyme inducers CYP3A4 (for example, rifampicin, St. John's wort) was not received, against the background of their simultaneous use regular blood pressure control is recommended.

    Beta-adrenoblockers with simultaneous application with amlodipine may cause an exacerbation of the course of CHF.

    Although no negative inotropic effects were usually observed in the study of amlodipine, nevertheless, some BCCCs can increase the severity of the negative inotropic effect of antiarrhythmic agents that cause lengthening of the interval QT (eg, amiodarone and quinidine).

    A single dose of 100 mg of sildenafil in patients with AH does not affect the pharmacokinetics of amlodipine.

    The repeated use of amlodipine in a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.

    Ethanol (drinks containing alcohol): amlodipine at a single and repeated application in a dose of 10 mg does not affect the pharmacokinetics of ethanol.

    Neuroleptics and isoflurane increase the antihypertensive effect of dihydropyridine derivatives.

    With intravenous administration of dantrolene against amlodipine therapy, collapse, arrhythmias, a decrease in the force of the heart contractions and hyperkalemia are possible.

    Calcium preparations can reduce the antihypertensive effect of BCCC.

    With the simultaneous use of amlodipine with lithium preparations, an increase in the manifestation of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, and tinnitus) is possible. Amlodipine does not change the pharmacokinetics of cyclosporine.

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

    Has no significant effect on the effect of warfarin (prothrombin time). Cimetidine does not affect the pharmacokinetics of amlodipine.

    In studies in vitro Amlodipine does not affect the binding of blood proteins to digoxin, phenytoin, warfarin and indomethacin.

    Simultaneous single intake of 240 mg of grapefruit juice and 10 mg of amlodipine by mouth is not accompanied by a significant change in the pharmacokinetics of amlodipine. A single intake of aluminum or magnesium-containing antacids does not significantly affect the pharmacokinetics of amlodipine.

    Losartan

    As with the use of other agents that block the formation of angiotensin II and its effects, the simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium and potassium-containing salt substitutes can lead toincrease in potassium in the blood serum.

    As with the use of other drugs that affect the excretion of sodium, losartan can reduce the excretion of lithium, so when lithium and ARA II are used simultaneously, the concentration of lithium in serum should be monitored carefully.

    In some patients with impaired renal function who have been treated with NSAIDs, including selective inhibitors of cyclooxygenase-2 (COX-2), simultaneous use of ACE inhibitors and / or APA II, including losartan, can cause further impairment of kidney function until the development of acute renal failure (ARF). Usually, this effect is reversible. NSAIDs, including selective inhibitors of COX-2, can reduce the effect of ARA II, including losartan. Therefore, the antihypertensive effect of APA II may be weakened by the simultaneous use of NSAIDs, in particular selective COX-2 inhibitors. Therefore, simultaneous use of amlodipine / losartan with NSAIDs should be performed with caution in patients with impaired renal function.

    Double blockade of RAAS (simultaneous use of ACE inhibitors and APA II) in patients with atherosclerosis,CHF or diabetes mellitus with target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including acute renal failure) compared with the use of a drug in one of these groups. Double blockade of RAAS is possible only in selected cases under careful control of kidney function. The simultaneous use of losartan with aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (KC less than 60 ml / min) and is not recommended in other patients.

    There were no pharmacokinetically significant interactions of losartan with such drugs as hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Taking rifampicin, an inducer of drug metabolism, reduces the concentration of losartan and its active metabolite in the blood plasma.

    In clinical studies, the use of two inhibitors of isoenzyme CYP3A4. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect on the pharmacokinetics of losartan when administered orally.

    Fluconazole, isoenzyme inhibitor CYP2C9, reduces the concentration of the active metabolite of losartan and increases the concentration of losartan in the blood plasma, however, the pharmacodynamic significance of the simultaneous use of losartan and inhibitors of the isoenzyme CYP2C9 not installed. It was shown that in patients not metabolizing losartan in the active metabolite, there is a very rare and specific defect isoenzyme CYP2C9. These data indicate that the metabolism of losartan to the active metabolite is primarily mediated by an isoenzyme CYP2C9, but not an isoenzyme CYP3A4.

    Special instructions:

    Patients with reduced BCC

    In patients with reduced BCC (eg, with high doses of diuretics, severe diarrhea, vomiting, and other conditions leading to hypovolemia), symptomatic arterial hypotension may develop at the onset of Lortense therapy. Before using Lortens, the BCC deficiency should be eliminated. For patients whose daily dose of losartan is 25 mg, the use of Lortens is not recommended (see section "Method of administration and dose").

    Special instructions and precautions related to amlodipine

    Due to prolonged T1 / 2, the vasodilatation, developed as a result of taking amlodipine, can persist even after its withdrawal. Thus, the use of another vasodilator after amlodipine withdrawal should be done with caution, individual dose assessment, dosage interval and active monitoring of the patient's condition are necessary.

    In the period of treatment, it is necessary to control body weight and intake of table salt, the appointment of an appropriate diet. It is necessary to maintain dental hygiene and frequent visits to the dentist (to prevent soreness, bleeding and gingival hyperplasia).

    Special instructions and precautions related to losartan

    Hyperkalemia (potassium content in the blood plasma> 5.5 mmol / l) was noted in 1.5% of patients taking losartan in the form of monotherapy. In none of these cases was it necessary to cancel the drug. Simultaneous use of potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium preparations, potassium-containing salt substitutes, as well as drugs, the reception of which can lead to an increase in the potassium content in the blood plasma (for example, heparin),with losartan should be justified (especially in elderly patients with impaired renal function), and the content of potassium in the blood plasma should be under control.

    The administration of losartan can lead to transient arterial hypotension, accompanied by shock, fainting and shortness of breath.

    Lortense should be used with caution in patients:

    - with a reduced BCC;

    - on a diet with restriction of table salt.

    Hypersensitivity reactions

    Patients with angioneurotic edema in the anamnesis (edema of the larynx, vocal cords, face, lips, pharynx and / or tongue) need control of the Lortense drug (see section "Side effect").

    Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

    Like all drugs that have a vasodilating effect, APA II should be used with caution in patients with aortic or mitral stenosis, GOKMP. Chronic heart failure

    As with other drugs that have an effect on RAAS, patients with CHF and with or without renal dysfunction, there is a risk of developing severe arterial hypotension or acute renal dysfunction.

    Since there is insufficient experience of using losartan in patients with CHF and concomitant severe renal dysfunction, in patients with severe heart failure (IV functional class by classification NYHA), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, Lortense should be used with caution in patients of these groups.

    Ischemic heart disease and cerebrovascular disease

    Like all drugs that have a vasodilating effect, ARA II should be used with caution in patients with coronary heart disease or cerebrovascular disease, as excessive reduction in blood pressure in this group of patients can lead to myocardial infarction or stroke.

    Primary hyperaldosteronism

    Since in patients with primary hyperaldosteronism, as a rule, there is no positive response to therapy with antihypertensive drugs that act by inhibiting RAAS, the use of Lortens is not recommended in this group of patients.

    Patients with hepatic insufficiency

    The data of pharmacokinetic studies indicate that in patients with cirrhosis of the liver a significant increase in the concentration of losartan in the blood plasma is observed. The use of Lortense is not recommended in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale), as well as in patients with hepatic insufficiency (less than 9 on the Child-Pugh scale), which recommended a decrease in the dose of losartan to 25 mg per day.

    Patients with renal insufficiency

    Due to inhibition of RAAS in some predisposed patients who took losartan, there were reversible changes in kidney function when the drug was withdrawn.

    In patients whose renal function may depend on the activity of RAAS (eg, with CHF III-IV functional class by classification NYHA), the use of ACE inhibitors was accompanied by oliguria and / or increasing azotemia and, rarely, acute renal failure and / or lethal outcome. A similar picture was observed with the use of losartan in such patients. In clinical studies, the use of ACE inhibitors in patients with single or bilateral renal artery stenosis led to an increase in the concentration of creatinine and residual urea nitrogen in the blood plasma.A similar effect was observed when taking losartan in this group of patients, it was reversible when the drug was withdrawn. Lortense should be used with caution in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney.

    Special information on excipients

    The Lortense preparation contains lactose, so it should not be used in the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

    Effect on the ability to drive transp. cf. and fur:

    Care should be taken when driving vehicles and working with other technical devices that require a high concentration of attention and speed of psychomotor reactions, taking into account the risk of developing dizziness.

    Form release / dosage:

    Film-coated tablets, 5 mg + 50 mg, 10 mg + 50 mg, 5 mg + 100 mg, 10 + 100 mg.

    Packaging:

    For 7 or 10 tablets in a contour acheikova packing of the combined material OPA / Al / PVC and aluminum foil.

    1, 2, 4, 8, 12 contour cell packs (7 tablets each) or 1, 3, 6, 9 contour cell packs (10 tablets each) together with instructions for use are placed in a pack of cardboard.
    Storage conditions:

    At a temperature of no higher than 25 ° C, in the original packaging.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002760
    Date of registration:15.12.2014
    The owner of the registration certificate:KRKA-RUS, LLC KRKA-RUS, LLC Russia
    Manufacturer: & nbsp
    Representation: & nbspKRKA KRKA Slovenia
    Information update date: & nbsp15.12.2014
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