Losartan-TAD - instructions for use, dose, side effects, contraindications

	12.5 mg	25 mg	50 mg	100 mg
Active substance: Losartan potassium	12.50 mg	25.00 mg	50.00 mg	100.00 mg
Excipients:
Zellactose *	18.225 mg	36.45 mg	72.90 mg	145.80 mg
Starch pregelatinized	6.25 mg	12.50 mg	25.00 mg	50.00 mg
Corn starch	6.25 mg	12.50 mg	25.00 mg	50.00 mg
Cellulose microcrystalline	6.25 mg	12.50 mg	25.00 mg	50.00 mg
Silicon colloid anhydrous	0.15 mg	0.30 mg	0.60 mg	1.20 mg
Magnesium stearate	0.375 mg	0.75 mg	1.50 mg	3.00 mg
Sheath:
Hypromellose	0.9025 mg	1.805 mg	3.61 mg	7.22 mg
Talc	0.0825 mg	0.165 mg	0.33 mg	0.66 mg
Propylene glycol	0.0700 mg	0.140 mg	0.28 mg	0.56 mg
Color quinoline yellow, E 104	0.0025 mg	0.020 mg	-	-
Titanium dioxide, E171	0.1925 mg	0.370 mg	0.78 mg	1.56 mg

* Zellactose - a mixture of lactose monohydrate and cellulose.

Description:

Tablets 12.5 mg. Oval, slightly biconvex tablets, covered with a film membrane from light yellow to yellow, with a bevel.

Tablets 25 mg. Oval, slightly biconvex tablets, covered with a film membrane, yellow, with a risk on one side and a facet.

Tablets 50 mg. Round, slightly biconvex tablets, covered with a film shell, white, with a risk on one side, with a bevel.

Tablets of 100 mg. Oval, slightly biconvex tablets, covered with a film coat, white.

Pharmacotherapeutic group:Angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

Mechanism of action

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. Losartan - highly effective when ingested angiotensin II receptor antagonist (type AT₁). Angiotensin II selectively binds to AT₁receptors found in many tissues (in the smooth muscle tissues of blood vessels, in the adrenal gland, in the kidneys and in the heart) and performs several important biological functions, including vasoconstriction and aldosterone release.Angiotensin II also stimulates proliferation of smooth muscle cells. Losartan and its pharmacologically active metabolite (E-3174) both in vitro and in vivo block all the physiological effects of angiotensin II, regardless of the source or route of synthesis. Unlike some peptide angiotensin II antagonists, losartan does not have the effects of an agonist.

Losartan selectively binds to AT₁receptors and does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit the angiotensin-converting enzyme (ACE), which is responsible for the destruction of bradykinin.

Consequently, effects that are not directly related to AT blockade₁-receptors, including bradykinin-mediated effects and development of edema (losartan - 1,7%, placebo - 1,9%), are not related to the action of losartan.

Pharmacodynamics

Because the losartan is a specific AT antagonist₁receptors of angiotensin II, it does not inhibit ACE (kinase II), an enzyme that inactivates bradykinin. A study comparing the effects of 20 mg and 100 mg of losartan with ACE inhibitor effects on the response to angiotensin I, angiotensin II and bradykinin showed that losartan blocks the effects of angiotensin I and angiotensin II, without affecting the effects of bradykinin, which is due to the specific mechanism of action of losartan. ACE inhibitors, on the contrary, block the response to angiotensin I and increase the severity of responses to bradykinin without affecting the severity of the response to angiotensin II, which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors.

The concentration of losartan and its active metabolite in the blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. As losartan and its active metabolite are antagonists of angiotensin II receptors, they both contribute to the antihypertensive effect.

Losartan does not affect vegetative reflexes and does not have a lasting effect on the concentration of noradrenaline in the blood plasma.

In patients with hypertension losartan in doses up to 150 mg / day does not cause clinically significant changes in the concentration of fasting triglycerides, total cholesterol (Xc) and high-density lipoprotein cholesterol (HDL-C). In the same doses losartan does not affect the concentration of glucose in the blood on an empty stomach.

Pharmacokinetics:

Suction

Ingestion losartan It is well absorbed and metabolized while "primary pass" through the liver, resulting in formation of the active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan is approximately 33%. Mean maximum concentrations (C_max) losartan and its active metabolite are achieved after 1 h and 3-4 h, respectively. The use of losartan with conventional food had no clinically significant effect on the profile of plasma concentrations of losartan.

Distribution

Lozartan and its active metabolite bind to plasma proteins (mainly albumins) by more than 99%. The volume of distribution of losartan is 34 liters. Losartan practically does not penetrate the blood-brain barrier.

Metabolism

Approximately 14% of the dose of losartan (with ingestion or intravenous (intravenous) administration) is converted to its active metabolite. After oral or intravenous administration of radiolabeled radiolabel¹⁴C losartan, the radioactivity of circulating blood plasma is due to the presence of losartan and its active metabolite.In addition to the active metabolite, biologically inactive metabolites are formed, including two basic, hydroxylated side chain butyl chains, and one secondary N-2-tetrazole-glucuronide.

Excretion

The plasma clearance of losartan and its active metabolite is about 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 taking losartan, about 4% of the dose is excreted unchanged by the kidneys and about 6% of the dose is excreted by the kidneys in the form of an active metabolite. Losartan and its active metabolite have a linear pharmacokinetics when ingested at doses up to 200 mg.

After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite half-life (T_1/2) about 2 and 6-9 hours, respectively. When taking the drug at a dose of 100 mg 1 time / day, there is no significant cumulation in the plasma of either losartan or its active metabolite.

The excretion of losartan and its metabolites occurs with bile and kidneys. After ingestion with radioactive carbon labeled ¹⁴C losartan, about 35% of radioactivity is found in urine and 58% in feces. After iv introduction of radioactive carbon labeled ¹⁴C losartan, approximately 43% of radioactivity is detected in urine and 50% in feces.

Pharmacokinetics in specific patient groups
Elderly patients

The concentrations of losartan and its active metabolite in blood plasma in elderly people with arterial hypertension do not differ significantly from the values of these parameters in younger patients with arterial hypertension.

Floor

Values of plasma concentrations of losartan in women with arterial hypertension were 2 times higher than the corresponding values for men with arterial hypertension. The concentrations of active metabolite in men and women did not differ. This apparent pharmacokinetic difference, however, has no clinical significance.

Patients with impaired liver function

When losartan was taken orally by patients with mild and moderate alcoholic cirrhosis, the concentration of losartan and its active metabolite in blood plasma was 5 and 1.7 times (respectively) higher than in young healthy male volunteers.

Patients with impaired renal function

The concentration of losartan in the blood plasma in patients with creatinine clearance (CC) above 10 ml / min did not differ from those in persons with normal renal function. When comparing the area of the pharmacokinetic curve "concentration-time" (AUC) in patients with normal renal function, the AUC of losartan in patients on hemodialysis was approximately 2-fold greater. Plasma concentrations of the active metabolite did not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite is not excreted in hemodialysis.

Indications:

- Arterial hypertension.

- Reducing the risk of developing cardiovascular disease and mortality in patients with hypertension and left ventricular hypertrophy.

- In patients with type 2 diabetes mellitus with proteinuria to slow the progression of renal failure, manifested by a decrease in the frequency of hypercreatininemia, the incidence of terminal end stage of chronic renal failure (CRF), requiring dialysis or kidney transplantation, mortality rates, and a decrease in proteinuria.

- Chronic heart failure in combination therapy with ineffective treatment with ACE inhibitors.

Contraindications:Hypersensitivity to any of the components of the drug, primary hyperaldosteronism, severe hepatic insufficiency (more than 9 on the Child-Pugh scale), pregnancy, breastfeeding, age under 18 (safety and efficacy not established), lactose intolerance, lactase deficiency, glucose -galactose malabsorption, simultaneous use with aliskiren-containing agents in patients with diabetes mellitus and / or patients with impaired renal function (glomerular filtration rate (GFR) of less than 60 ml / min / m²).

Carefully:Arterial hypotension, aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy, heart failure with concomitant severe renal insufficiency, severe chronic heart failure (NYHA functional class IV), heart failure with life-threatening arrhythmias, ischemic heart disease, cerebrovascular disease, renal / hepatic failure,bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, condition after kidney transplantation, liver failure (less than 9 on the Child-Pugh scale), hyperkalemia, dehydration, angioedema in the anamnesis, incl. associated with the use of ACE inhibitors (a special group of risk are patients of the Negroid race), simultaneous administration of potassium or potassium-sparing diuretics, simultaneous administration with aliskiren-containing drugs, simultaneous administration of non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors (COX-2) , lithium preparations.

Pregnancy and lactation:

The use of Losartan-TAD during pregnancy is contraindicated.

The use of drugs acting on the RAAS in the second and third trimesters of pregnancy can cause serious developmental disorders and even death of the developing fetus, therefore, when establishing pregnancy, Lozartan-TAD should be discontinued immediately.

Renal perfusion in the fetus, depending on the development of RAAS, appears in the second trimester; The risk to the fetus increases if Losartan-TAD is administered in the second or third trimester of pregnancy.

It is not recommended to take Losartan-TAD during breast-feeding. Experience with losartan in lactating women is not, and it is not known whether the drug is excreted in breast milk. If you need to take Lozartan-TAD, breastfeeding should be interrupted.

Dosing and Administration:

Inside, regardless of food intake. Losartan-TAD can be taken in combination with other antihypertensive agents.

Arterial hypertension

The standard initial and maintenance dose for most patients is 50 mg 1 time / day. The maximum hypotensive effect is achieved 3-6 weeks after the start of therapy. In some patients, to achieve a greater effect, the dose may be increased to a maximum daily dose of 100 mg of the drug Losartan-TAD 1 time / day.

In patients with reduced circulating blood volume (BCC) (for example, when taking large doses of diuretics), the initial dose of the drug should be reduced to 25 mg 1 time / day (see Special instructions).

There is no need to select an initial dosage in the elderly and patients with renal insufficiency, including patients on hemodialysis.

Patients with a history of liver disease are recommended to prescribe the drug in lower doses.

Reduced risk of associated cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy

The standard initial dose of the drug is 50 mg 1 time / day. It is recommended to add hydrochlorothiazide in low doses or increase the dose of the drug Losartan-TAD to a maximum daily dose of 100 mg 1 time / day, taking into account the degree of lowering blood pressure (BP).

Kidney protection in patients with type 2 diabetes and proteinuria

The standard initial dose of the drug is 50 mg 1 time / day. In the future, it is recommended to increase the dose of Lozartan-TAD to a maximum daily dose of 100 mg 1 time / day, taking into account the degree of BP reduction. Lozartan-TAD can be prescribed in combination with other antihypertensive agents (diuretics, blockers of "slow" calcium channels, alpha and beta adrenoblockers, antihypertensive agents for ingestion of central action), insulin and other hypoglycemic agents (sulfonylurea derivatives,glitazones and glucosidase inhibitors).

Chronic heart failure

The initial dose of the drug is 12.5 mg 1 time / day. Typically, the dose is titrated at a weekly interval (ie, 12.5 mg / day, 25 mg / day, 50 mg / day, 100 mg / day) to a maximum (only for this indication) 150 mg dose 1 time / day depending on the individual portability.

Side effects:

Depending on the frequency of occurrence, the following groups of side effects are identified: very often (≥ 1/10), often (≥ 1/100, <1/10), infrequently (≥ 1/1000, <1/100), rarely (≥ 1 / 10000, <1/1000), very rarely (<1/10000), including individual messages, the frequency is unknown - can not be determined from the available data.

From the nervous system and sensory organs: often - dizziness loss of consciousness; infrequently - drowsiness, headache, sleep disturbances, paresthesia; the frequency is unknown - migraine, taste disorders, depression, ringing in the ears.

From the cardiovascular system: infrequently - orthostatic hypotension (dose-dependent), palpitations, angina pectoris; rarely - a syncope, a ciliary arrhythmia, an acute infringement of a cerebral circulation.

From the respiratory system: infrequently - cough, dyspnea.

From the digestive system: infrequently - abdominal pain, constipation, diarrhea, nausea, vomiting; rarely - hepatitis; the frequency is unknown - pancreatitis, liver function disorders.

From the genitourinary system: often - renal failure, impaired renal function; frequency unknown - erectile dysfunction / impotence.

From the musculoskeletal system: frequency unknown - myalgia, arthralgia, rhabdomyolysis.

From the skin: infrequently - hives, skin rashes, itching, photosensitivity.

Allergic reactions: rarely - anaphylactic reactions, angioedema, incl. face, lips, pharynx and / or tongue, allergic vasculitis, including the purple Shenlen Genoch.

Laboratory indicators: often - hyperkalemia, increased concentration of urea and creatinine in the blood, hypoglycemia; rarely - increased activity of "liver" transaminases; frequency unknown - anemia, thrombocytopenia, hyponatremia.

Are common: infrequently - asthenia, fatigue, swelling, a feeling of general discomfort.

Overdose:

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

Treatment: forced diuresis, symptomatic therapy.

Lozartan and its active metabolite are not removed from the bloodstream during hemodialysis.

Interaction:

Strengthens (mutually) the effect of other antihypertensive drugs (diuretics, βadrenoblokatorov, sympatholytics).

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

Because the losartan predominantly metabolized with the participation of the CYP2C9 isoenzyme, potential interactions are possible with inducers and inhibitors of the CYP2C9 isoenzyme. Thus, in the presence of the inhibitor of the isoenzyme CYP2C9 fluconazole AUC losartan increases by 70%, while the AUC of its active metabolite decreases by 40-50%. With simultaneous administration of phenobarbital AUC losartan, as well as its active metabolite, increases by 20% (not clinically significant). Rifampicin leads to a decrease in AUC of losartan by 30%, active metabolite - by 40%.

Fluvastatin, a weak inhibitor of the isoenzyme CYP2C9, does not change the pharmacokinetic parameters of losartan or its metabolite. Cimetidine leads to an increase in AUC of losartan by 18%; and does not affect the AUC of the active metabolite.

The biotransformation of losartan is not affected ketoconazole, inhibitor of the isoenzyme CYP3A4. But, erythromycin, which also inhibits the isoenzyme CYP3A4, increases the AUC of 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 hyperkalemia, and can not be recommended for use against 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, so you should regularly monitor the lithium content in the blood.

The antihypertensive effect of losartan can be weakened in the presence of NSAIDs, including selective inhibitors of 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 is the simultaneous use of an angiotensin II receptor antagonist with an ACE inhibitor or aliskiren-containing agents (containing a direct inhibitor of renin- aliskiren) - 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. Lozartan-TAD should not be used concurrently with aliskiren-containing drugs in patients with diabetes mellitus and / or patients with impaired renal function (GFR less than 60 mL / min / m²).

Special instructions:

Hypersensitivity reactions

Treatment of patients with angioneurotic edema in a history should be started under the strict supervision of a doctor in a hospital. Angioedema occurs more often in patients of the Negroid race.

Arterial hypotension (disturbance of water-electrolyte balance or decrease in BCC)

In patients with reduced BCC (eg, receiving treatment with large doses of diuretics, diets with restriction of table salt, diarrhea, vomiting), symptomatic arterial hypotension may occur. Correction of such conditions should be performed prior to the appointment of Lozartan-TAD or to begin treatment with a lower dose (see Dosage and Administration).

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

During treatment with Losartan-TAD, patients should not take potassium or potassium substitutes for table salt without first consulting with the doctor.

Impaired liver function

Data from pharmacokinetic studies indicate that the concentration of losartan in the blood plasma of patients with cirrhosis increases significantly, so patients with a history of liver disease should be prescribed a drug at a lower dose (see Dosage and Administration).

Impaired renal function

Due to the inhibition of RAAS, some susceptible patients experienced changes in kidney function, including renal failure; These changes may disappear after discontinuation of treatment.

Some drugs that affect RAAS can increase the concentration of blood urea and serum creatinine in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney. It has been reported that such effects occur when taking losartan; changes in kidney function may disappear upon discontinuation of therapy.

In patients with a renal function dependent on RAAS (ie, with severe chronic heart failure), treatment with ACE inhibitors in some cases was accompanied by the development of oliguria and / or increasing azotemia, and acute renal failure (rarely) and / or deaths .Similar outcomes were reported in the treatment of this category of patients with losartan.

There is insufficient experience with losartan in patients with heart failure and concomitant severe renal failure, in patients with severe chronic heart failure (NYHA functional class IV), in patients with heart failure and symptomatic life-threatening arrhythmias. In these groups losartan should be used with caution and with βadrenoblockers.

In patients with cardiovascular and cerebrovascular diseases of an ischemic nature, an excessive decrease in blood pressure can lead to a heart attack / stroke. It is recommended that the medical control during dose titration.

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

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

Clinical studies have not revealed any difference in the safety and efficacy of losartan in elderly patients compared with younger patients.

Like other angiotensin II receptor antagonists, Losartan-TAD may not be effective in reducing blood pressure in patients with low plasma renin activity (in particular, in patients of the Negroid race compared to patients of other races).

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:Film-coated tablets, 12.5 mg, 25 mg, 50 mg and 100 mg.

Packaging:For 7, 10, 14 tablets in a planar cell package. 2 contour packs of 7 tablets, 1 contour pack of 14 tablets, 3, 6 or 9 contour packs of 10 tablets together with instructions for use are placed in a pack of cardboard.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:Tablets 12.5 mg: 2 years. Tablets 25 mg: 3 years. Tablets 50 mg and 100 mg: 5 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002482

Date of registration:29.05.2014

Expiration Date:29.05.2019

The owner of the registration certificate:TAD Pharma GmbHTAD Pharma GmbH Germany

Manufacturer: & nbsp

TAD PHARMA, GmbH Germany

Representation: & nbspTAD Pharma GmbHTAD Pharma GmbHRussia

Information update date: & nbsp03.04.2018

Illustrated instructions

Instructions

Losartan-TAD (Losartan-TAD)