Lotor - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 44.56 / 89.12 mg, lactose monohydrate 22.50 / 45.00 mg, pregelatinized starch 22.50 / 45.00 mg, croscarmellose sodium 6.00 / 12.00 mg, silicon dioxide colloid 1.44 / 2.88 mg, magnesium stearate 3.00 / 6.00 mg;

shell: fall off OY-S-7331 white (hypromellose-3sP-1.75 / 3.5 mg, giprolose 1.50 / 3.0 mg, titanium dioxide 1.00 / 2.0 mg, macrogol 6000-0.50 / 1.0 mg, hypromellose-50cP - 0.25 (0.5 mg).

Description:TOrifle, biconvex tablets, covered with a film shell from white to almost white with a risk on one side. On the fracture: from white to almost white.

Pharmacotherapeutic group:Angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

A hypotensive drug is a specific antagonist of angiotensin II receptors (type AT₁).

Angiotensin II is a potent vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and the decisive pathophysiological link in the development of hypertension. Angiotensin II performs several important biological functions, including the influence on the secretion of aldosterone by the adrenal cortex, the proliferation of smooth muscle cells of the vessels, the activation of the sympathetic-adrenal system. Most physiological effects of angiotensin II are mediated AT₁-receptors, localized mainly in the smooth muscles of blood vessels, in the heart, liver, adrenal cortex, kidneys, lungs.

Lozartan and its active metabolite (E-3174) as in vitro, and in vivo prevent stimulation AT₁-receptors and thereby block the effects of angiotensin II, regardless of the pathway of its formation. Losartan reduces overall peripheral vascular resistance (OPSS) and blood pressure (BP), reduces afterload, reduces pressure in a small circle of blood circulation,the concentration of norepinephrine and aldosterone in the blood, has a diuretic effect. Prevents hypertrophy of the myocardium, increases tolerance to physical activity in patients with chronic heart failure.

After a single dose, the antihypertensive effect (decreases both systolic and diastolic blood pressure) reaches a maximum after 6 hours, then gradually decreases within 24 hours. A stable antihypertensive effect develops 3-6 weeks after the start of the drug.

Unlike some peptide angiotensin II antagonists, losartan does not have the effects of an agonist. Selectively affects the receptors AT₁ does not block and does not affect other hormonal receptors and ion channels. Does not inhibit angiotensin-converting enzyme (ACE) (kininase II); an enzyme that prevents the destruction of bradykinin, thus preventing the potentiation of the effects of the latter.

In patients with hypertension losartan in doses up to 150 mg / day does not lead to clinically significant changes in the level of triglycerides (fasting), total cholesterol and high-density lipoproteins; does not affect the concentration of glucose (fasting).In patients with arterial hypertension and proteinuria (≥ 2 g / 24 hours), not suffering from diabetes, receiving losartan in a dose of 50-100 mg, after 8 weeks of treatment there is a significant decrease in proteinuria, a significant decrease in immunoglobulins (IgG) and albumin in urine; Stabilization of the glomerular filtration rate is noted.

Pharmacokinetics:

Quickly absorbed from the gastrointestinal tract. Admission with food does not have a clinically significant effect on the profile of plasma concentrations of losartan.

Bioavailability with ingestion is 33%. Losartan is susceptible to the effect of "first passage" through the liver, resulting in up to 14% of the ingested drug converted to the active carboxylated metabolite (E-3174), antagonistic activity of which with respect to the receptors AT₁ 10-40 times higher than that of losartan.

The time to reach the maximum concentration (TC_m_Oh) losartan is 1-2 h, the active metabolite is 3-4 h; half-life (T_1/2) - 1.5-2 hours and 6-9 hours, respectively. The pharmacokinetics of losartan (in doses up to 200 mg) and its active metabolite is linear.

The connection with plasma proteins is 99%.The volume of distribution is 34 liters.

Metabolized by carboxylation with the participation of isoenzyme CYP2C9 systems of cytochrome P450 with the formation of active and inactive metabolites; among the latter - the two basic, formed as a result of hydroxylation of the side butyl chain, and one secondary - N-2-tetrazole-glucuronide.

Plasma concentrations of losartan and its active metabolite are reduced polyexponentially. The plasma clearance of losartan and its active metabolite is about 600 ml / min and 50 ml / min, the renal clearance is 74 ml / min and 26 ml / min, respectively. A drug is produced with bile and through the kidneys. Through the kidneys, 35% (of which 4% - in the form of an unchanged drug) are excreted; The rest of the amount (about 60%) is through the intestine.

With a dosage regimen of 100 mg per day, cumulation of losartan and its active metabolite is not observed.

Lozartan and its active metabolite are not removed during hemodialysis.

Patients of advanced age (over 65 years)

In elderly patients with hypertension the concentration of the drug in plasma does not differ from that in young men with arterial hypertension.

Patients with impaired hepatic function

After oral administration of losartan in patients with cirrhosis of the liver (moderate to moderate severity), the concentration of losartan in the blood plasma is 5 times, and the active metabolite is 1.7 times higher than similar concentrations in healthy volunteers. Total plasma clearance of the drug y patients with hepatic insufficiency are less than in healthy volunteers by 50%, bioavailability is twice as high. In connection with these features, correction of the dosing regimen is required.

Patients with impaired renal function

In patients with impaired renal function with creatinine clearance (CK) exceeding 10 ml / min, the concentration of losartan in plasma does not differ from that in patients with preserved renal function. The concentrations of the active metabolite in the blood plasma of patients with impaired renal function and patients on hemodialysis do not differ.

Patients on hemodialysis in relation to patients with preserved renal function AUC (the area under the concentration-time curve) of losartan is 2 times greater. Nevertheless, correction of the dosing regimen is not required.

Indications:

- Arterial hypertension.

- Chronic heart failure (as part of combination therapy, with intolerance or ineffective therapy with ACE inhibitors).

- Reducing the risk of developing cardiovascular diseases (including stroke) and mortality in patients with hypertension and left ventricular hypertrophy.

- Protection of the kidneys in patients with type 2 diabetes mellitus with proteinuria, slowing the progression of renal failure, manifested by a decrease in the frequency of hypercreatininemia, the incidence of end-stage renal disease (requiring dialysis or kidney transplantation), mortality, and a decrease in proteinuria.

Contraindications:

Hypersensitivity to losartan and / or accessory components of the drug, primary hyperaldosteronism, severe hepatic insufficiency (more than 9 on the Child-Pugh scale), pregnancy, lactation, children and adolescents under 18 years (safety and efficacy not established), lactase deficiency , galactosemia, glucose-galactose malabsorption syndrome.

Carefully:

Arterial hypotension, stenosis of the aortic aorta, hypertrophic obstructive cardiomyopathy,renal / hepatic insufficiency, bilateral stenosis of the renal arteries or stenosis of the single kidney artery, hyperkalemia, dehydration, angioedema in the anamnesis, including those associated with the use of ACE inhibitors, simultaneous administration of potassium or potassium-sparing diuretics, simultaneous administration of ACE inhibitors, simultaneous use of non-steroidal anti-inflammatory drugs drugs (NSAIDs), including COX-2 inhibitors, simultaneous use of lithium drugs, angioedema (history) on the background of an inhibitor s ACE (a special group of risk are patients of the Negroid race).

Pregnancy and lactation:

During pregnancy, the lotor is contraindicated. At the same time, the risk for the fetus in the first trimester is lower than in the II-III trimesters, since renal perfusion in the fetus, depending on RAAS, appears in the II trimester.

In the first trimester, it is not recommended to appoint Lotor. However, in those extremely rare cases (less than one in a thousand women), when the use of all other antihypertensive drugs is not possible, the drug can be administered under close medical supervision, including a weekly ultrasound examination.In case of signs of oligohydramnion, treatment with an angiotensin II receptor antagonist should be discontinued.

Since the medicines that affect RAAS are II-III trimesters of pregnancy can lead to disruption in the development and / or death of the fetus, when establishing the fact of pregnancy, the taking of Lotor should be stopped immediately.

For newborns and infants who have been in utero exposed to the angiotensin II receptor antagonist, careful monitoring is recommended for the timely detection of a marked decrease in blood pressure, oliguria, and hyperkalemia.

It is not known whether losartan with breast milk. Nursing mothers, Lothor is contraindicated. If necessary, breast-feeding should be discontinued.

Dosing and Administration:

Inside. Tablets are swallowed, not liquid, squeezed with water, regardless of food intake; The frequency of reception is 1 time per day, preferably at the same time, in the morning.

Arterial hypertension

The standard initial and maintenance dose is 50 mg / day. If necessary, the daily dose can be increased to 100 mg.If a single dose of the drug does not achieve the target blood pressure level, you should divide the daily dose into 2 divided doses (25 mg each (1/2 50 mg tablets) twice a day, or 50 mg twice a day).

Chronic heart failure

The initial dose for patients with chronic heart failure is 12.5 mg once a day (you can use losartan in tablets of 25 mg with a risk). The dose is titrated 2 times, depending on the patient's tolerability, with a weekly interval (ie 12.5, 25, 50 mg / day) to an average maintenance dose of 50 mg / day (12.5 mg or 25 mg tablets are used with risk, see also section "Special instructions").

In elderly patients and in patients with renal insufficiency there is no need to adjust the initial dose.

Reducing the risk of cardiovascular disease and mortality the patients with hypertension and left ventricular hypertrophy: the initial dose is 50 mg once a day, further it is recommended to additionally appoint hydrochlorothiazide or increase the dose to 100 mg once a day (taking into account the degree of depression of blood pressure).

Diabetes mellitus type 2 with proteinuria: the initial dose is 50 mg once a day with a further increase in the dose to 100 mg / day (taking into account the degree of depression of blood pressure).

For patients with reduced circulating blood volume (BCC), for example, receiving high doses of diuretics, an initial dose of 25 mg / day is recommended (1/2 tablets of 50 mg).

For patients with impaired hepatic function an initial dose of 25 mg / day is recommended (1/2 tablets of 50 mg).

For patients with moderate renal impairment (SC 20-50 ml / min) do not require dose adjustment.

Side effects:

From the nervous system and sense organs: 1% and more - dizziness, headache, asthenia, fatigue; less than 1% - sleep disorders, drowsiness, paresthesia, migraine, depression, loss of consciousness, ringing in the ears, a violation of taste.

From the side of the cardiovascular system: less than 1% - orthostatic hypotension (dose-dependent), palpitations, arrhythmia, angina pectoris, acute cerebrovascular accident.

From the respiratory system: 1% and more - cough *, infections of the upper respiratory tract (fever, sore throat, sinusopathy *, sinusitis, pharyngitis); less 1% - dyspnoea.

From the digestive system: 1% or more - nausea, diarrhea *, abdominal pain; less than 1% - vomiting, constipation, impaired liver function, hepatitis.

From the genitourinary system: less than 1% - urinary tract infections, renal dysfunction, acute renal failure, decreased potency.

From the side of the musculoskeletal system: 1% or more - myalgia *, back pain; less than 1% - arthralgia, rhabdomyolysis.

From the skin: less than 1% - skin hyperemia, photosensitivity.

Allergic reactions: less than 1% - hives, skin rash, itching, angioedema edema, incl. face, lips, pharynx and / or tongue, allergic vasculitis, purple Shenlaine-Genocha.

Other: more than 1% - hyperkalemia; less 1% - increased activity of "hepatic" transaminases, increased urea and creatinine in the blood, hypoglycemia, hyponatremia, anemia, thrombocytopenia.

* The frequency of development is comparable with placebo.

Overdose:

Symptoms: marked decrease in blood pressure and tachycardia; Bradycardia can occur due to parasympathetic stimulation.

Treatment: forced diuresis, symptomatic therapy; Hemodialysis is ineffective.

Interaction:

Strengthens (mutually) the effect of other antihypertensive drugs (diuretics, β-blockers, sympatholytics).

Tricyclic antidepressants, antipsychotics, baclofen, amifostine, increase the antihypertensive effect of losartan.

Because the losartan predominantly metabolized with the participation of isoenzyme CYP2C9, potential interactions are possible with the modulators of the latter. Thus, in the presence of an isoenzyme inhibitor CYP2C9 fluconazole AUC Lozartan increases by 70%, while AUC its active metabolite is reduced by 40-50%.

With simultaneous reception with phenobarbital AUC losartan, as well as its active metabolite, increases by 20% (is not clinically significant).

Rifampicin leads to a decrease AUC losartan by 30%, active metabolite - by 40%.

Fluvastatin, a weak isoenzyme inhibitor CYP2C9, does not change the pharmacokinetic parameters of losartan or its metabolite.

Cimetidine leads to an increase AUC losartan by 18% and does not affect AUC active metabolite.

The biotransformation of losartan is not affected ketoconazole, inhibitor of isoenzyme CYP3A4. However, erythromycin, which also inhibits the isoenzyme CYP3A4, contributes to an increase AUC losartan by 30% (not clinically significant).

There was no pharmacokinetic or pharmacodynamic interaction with warfarin, digoxin, hydrochlorothiazide.

Potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes increase the risk of hyperkalaemia and can not be recommended for use with losartan (see "Special instructions").

Like other agents that affect the excretion of sodium, losartan may lead to a delay in the excretion of lithium preparations, therefore, the concentration of lithium in the blood should be monitored regularly.

The antihypertensive effect of losartan may be weakened in the presence of non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2).

The simultaneous use of losartan, like other angiotensin II receptor antagonists, with NSAIDs may lead to impaired renal function and acute renal failure, hypernatremia; especially in patients with initial renal dysfunction, in patients with reduced BCC (or taking diuretics), in patients with age-related renal impairment (over 65 years).

Double blockade of RAAS - concomitant use of an angiotensin II receptor antagonist with an ACE inhibitor leads to a significant increase in the incidence of adverse events such as hypotension, syncope, hyperkalemia, renal dysfunction,acute renal failure. The highest risk is in patients with atherosclerosis, heart failure, diabetes mellitus (with any complication). The question of the application of a double blockade of RAAS (for example, by simultaneous administration of an ACE inhibitor with an angiotensin II receptor antagonist) should be addressed individually, with careful monitoring of renal function.

Special instructions:

Treatment of patients with angioneurotic edema in the anterior history should be started under the strict supervision of a doctor in a hospital setting. Angioedema occurs more often in patients of African-Caribbean origin.

After taking the first dose of Lotor, as with the next increase in the dose during the selection of the optimal dose, it is possible to develop symptomatic hypotension; with a greater probability - with initially lowered BCC due to therapy with diuretics, diets with restriction of table salt, diarrhea and vomiting. Before starting treatment with Lotor, it is necessary to replace BCC and normalize electrolyte disturbances or start treatment at a relatively low dose.

Since in patients with type 2 diabetes mellitus complicated by nephropathy, the risk of developing hyperkalemia is increased, periodic monitoring of potassium content in the blood and creatinine clearance should be provided.Similar monitoring should be provided in case of impaired renal function, which, as a rule, is accompanied by a violation of the electrolyte balance; and especially carefully monitor these indicators in patients with heart failure with concomitant renal dysfunction (KK 30-50 ml / min).

Simultaneous intake of potassium supplements, potassium-containing salt substitutes, potassium-sparing diuretics or other drugs that increase the content of potassium ions in the blood (for example, heparin) - only according to the doctor's prescription.

Given the pharmacokinetic characteristics of losartan in patients with cirrhosis of the liver, in the presence of liver disease in history, as with moderate and moderate hepatic insufficiency, Lotor should be prescribed in lower doses. Data on the safety of Lotor in patients with severe hepatic insufficiency do not. Drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Impaired renal function after reversal of Lothor reversible.The experience of using Lotor in patients after kidney transplantation is not present. Similarly, a high risk of developing these adverse events occurs in patients with heart failure, combined with impaired renal function.

In patients with severe chronic heart failure, Lothor, as well as other drugs that affect RAAS, can lead to severe arterial hypotension and acute renal failure. There are some reports of the development of oliguria and / or increasing azotemia and acute renal failure, including fatal.

There is insufficient experience of using Lotor in patients with heart failure with concomitant severe renal insufficiency, in patients with severe chronic heart failure (IV functional class by classification NYHA), in patients with heart failure and symptomatic life-threatening arrhythmias. Caution should be exercised in these groups with the Lottor βadrenoblockers.

In patients with cardiovascular and cerebrovascular diseases of an ischemic nature, an excessive decrease in blood pressure can lead to a stroke.It is recommended that the doctor check the titration dose.

Patients with primary hyperaldosteronism do not respond to therapy with antihypertensive drugs, the mechanism of action of which is mediated through RAAS, and therefore Lotor should not be prescribed for this disease.

Safety and efficacy of the drug in children are not established.

Clinical studies have not revealed any differences in the safety and efficacy of Lotor in elderly patients.

Like other angiotensin II receptor antagonists, Lothor may not be effective in reducing blood pressure in patients with low plasma renin activity (particularly in black patients compared to patients in other races).

This dosage form is not intended for dividing into 4 parts, accordingly it is not intended to obtain a minimum initial dose of 12.5 mg.

Effect on the ability to drive transp. cf. and fur: Care must be taken when driving vehicles or doing other work that requires increased attention, since the development of unwanted reactions such as dizziness and drowsiness is possible.

Form release / dosage:

Tablets, film-coated, 50 mg and 100 mg.

Packaging:

When packing on Hemofarm AD, Serbia

For 14 tablets in a planar cell package (blister) from a polyvinyl chloride / polyvinylidene chloride film and aluminum foil. For 2 blisters together with instructions for medical use in a pack of cardboard.

When packing with Hemofarm, Russia

For 10 or 14 tablets in a planar cell package (blister) from a polyvinylchloride / polyvinylidene chloride film and foil aluminum. For 3 blisters for 10 tablets or 2 blisters for 14 tablets together with instructions for medical use in a pack of cardboard.

Storage conditions:

In a dry, dark place at a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001755

Date of registration:02.07.2012 / 15.05.2014

Expiration Date:02.07.2017

Date of cancellation:2017-09-13

The owner of the registration certificate:Hemofarm ADHemofarm AD Serbia

Manufacturer: & nbsp

HEMOFARM, A.D. Serbia

Representation: & nbspSTADA CISASTADA CISARussia

Information update date: & nbsp13.09.2017

Illustrated instructions

Instructions

Lothor (Lotor)