Lozartan Canon - instructions for use, dose, side effects, contraindications

Excipients: corn starch 25.4 mg, croscarmellose sodium 5.5 mg, mannitol 30 mg, magnesium stearate 1 mg, povidone 3.1 mg, microcrystalline cellulose 25 mg;

film sheath: Rip off white 4 mg, including: hypromellose (hydroxypropylmethylcellulose) 1.35 mg, giprolose (hydroxypropyl cellulose) 1.35 mg, talc 0.8 mg, titanium dioxide 0.5 mg.

Dosage of 100 mg

1 tablet, film-coated, 100 mg contains:

active substance: Losartan potassium 100 mg;

Excipients: corn starch 50.8 mg, croscarmellose sodium 11 mg, mannitol 60 mg, magnesium stearate 2 mg, povidone 6.2 mg, microcrystalline cellulose 50 mg;

film sheath: Fill white with 8 mg, including: hypromellose (hydroxypropylmethylcellulose) 2.7 mg, giprolose (hydroxypropyl cellulose) 2.7 mg, talc 1.6 mg, titanium dioxide 1 mg.

Description:Tablets are round, biconvex, covered with a film coat of white or almost white color. On the cross-section - almost white.

Pharmacotherapeutic group:Angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

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 at ingestion selective antagonist of angiotensin II receptors (type AT₁). Angiotensin II selectively binds to AT_1-receptors found in many tissues (in the smooth muscle tissues of the vessels, in the adrenal, kidney and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the 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 that play an important role in regulating the function of the cardiovascular system (CVS). Besides, losartan does not inhibit the angiotensin-converting enzyme (ACE) responsible for the destruction of bradykinin. Consequently, effects that are not directly related to AT blockade₁-receptors, including bradykinin-mediated effects and the development of peripheral edema (losartan -1.7%, placebo - 1.9%), are not related to the action of losartan.

Reduces the overall peripheral resistance of blood vessels (OPSS), the concentration in the blood of norepinephrine and aldosterone, blood pressure (BP), pressure in the "small" range of blood circulation; reduces afterload, has a diuretic effect. Prevents development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure (CHF).When taking losartan, the plasma activity of renin (PAR) increases, which leads to an increase in angiotensin II in the blood plasma. After a single dose of antihypertensive effect (decreases systolic and diastolic blood pressure) reaches a maximum after 6 hours, then within 24 hours gradually decreases. In the course of treatment, antihypertensive activity and decrease in plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, which indicates effective blockade of angiotensin II receptors. However, after replacing losartan, the plasma renin activity and angiotensin II level decreased to the baseline values observed after the drug was administered 3 days later.

AND losartan, and its active metabolite have a higher affinity for AT receptors₁ than to AT receptors₂. The active metabolite is 10-40 times more active than losartan.

Pharmacokinetics:

Suction

Ingestion losartan is well absorbed from the gastrointestinal tract (GIT) and at the same time is metabolized by "primary passage" through the liver by carboxylation with the participation of the isoenzyme CYP2C9 to form an active metabolite.

Systemic bioavailability of losartan is approximately 33%.

The maximum concentration of losartan and its active metabolite is reached in the blood serum after approximately 1 hour and 3-4 hours after ingestion, respectively. Eating does not affect the bioavailability 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 (BBB).

Metabolism

Approximately 14% of the dose of losartan, administered intravenously or by mouth, is converted to its active metabolite. After ingestion 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 demonstrate 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 of approximately 2 and 6-9 hours, respectively. With the dosing regimen of 100 mg once a day, there is no significant cumulation in the plasma of either losartan or its active metabolite.
The excretion of losartan and its metabolites occurs through the intestine 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 intravenous administration 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 concentration of losartan and its active metabolite in blood plasma in elderly male patients with arterial hypertension do not differ significantly from the values of these parameters in male patients of younger age with arterial hypertension.

Floor: the plasma concentrations of losartan in women with arterial hypertension were 2 times higher than the corresponding values in 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 hepatic function: when losartan was administered orally to patients with mild and moderate alcoholic cirrhosis, the concentration of losartan and its active metabolite in blood plasma was 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 (CC) above 10 ml / min did not differ from those in patients with unchanged renal function. When comparing the area under the concentration-time curve (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 on hemodialysis. Losartan and its active metabolite are not excreted by hemodialysis.

Indications:

- Arterial hypertension.

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

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

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

Contraindications:

- Hypersensitivity to the active substance or to other components of the drug.

- Arterial hypotension.

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

- Primary hyperaldosteronism.

- Simultaneous use with aliskiren in patients with diabetes mellitus and patients with renal insufficiency (creatinine clearance less than 60 ml / min).

- Pregnancy, the period of breastfeeding.

- Age under 18 years (efficiency and safety not established).

Carefully:

- Violation of the water-electrolyte balance of blood (hyponatremia, hypochloraemic alkalosis, hypomagnesemia, hypokalemia, hyperkalemia).

- Reduction of the volume of circulating blood (BCC).

- Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, renal failure.

- Condition after kidney transplantation (no experience of application).

- 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 diseases.

- Liver failure (less than 9 on the Child-Pugh scale).

- Angioedema in history.

Pregnancy and lactation:

The drug Losartan Canon is contraindicated in pregnancy. At the same time, the risk for the fetus in the first trimester is lower than in the II-II trimesters, since renal perfusion in the fetus, depending on the renin-angiotensin-aldosterone system (RAAS), appears in the II trimester.

In the first trimester, the drug Losartan Canon is not recommended. 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 may be administered under close medical supervision, including a weekly ultrasound examination of the fetus. In case of signs of oligohydramnion, treatment with an angiotensin II receptor antagonist should be discontinued.

The use of angiotensin II receptor antagonists in the II or III trimesters of pregnancy has a toxic effect on the fetus (decreased kidney function, development of oligohydramnion, slowing ossification of the skull bones) and newborn (kidney failure, arterial hypotension, hyperkalemia).

Since drugs acting on RAAS in the II-III trimesters of pregnancy can lead to disruption of development and / orfetal death, when establishing the fact of pregnancy, the drug Lozartan Canon 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, so the drug Losartan Canon is contraindicated during breastfeeding. If necessary, breast-feeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake. Tablets are swallowed, not liquid, squeezed with water. Multiplicity of admission - 1 time / day, preferably at the same time, in the morning.

Arterial hypertension

The initial and maintenance dose is 50 mg / day. If necessary, the daily dose can be increased to a maximum of 100 mg. If a single dose of the drug does not provide the target level of blood pressure, the daily dose should be divided into 2 divided doses: 25 mg (losartan in 25 mg tablets or 50 mg tablets with risk) 2 times a day or 50 mg twice a day .

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

The initial dose of the drug is 50 mg 1 time / day. In the future, you can add hydrochlorothiazide in low doses or increased dose of the drug Lozartan Canon to a maximum of 100 mg in one or two doses, taking into account the decrease in blood pressure.

Chronic heart failure

The initial dose for patients with chronic heart failure is 12.5 mg (losartan is possible in tablets of 25 mg with a risk) 1 time / day. The dose is titrated 2 times, depending on the tolerance of the drug to the patient, with a weekly interval, i.е. 12.5 mg / day, 25 mg / day, 50 mg / day to an average maintenance dose of 50 mg / day.

In elderly patients with renal insufficiency, dose adjustment is not required.

In patients with type 2 diabetes mellitus with proteinuria to slow the progression of renal failure

The initial dose is 50 mg 1 time / day with a further increase in the dose to a maximum of 100 mg / day (in view of the degree of BP reduction) in one or two doses.

Special patient groups

In patients with reduced circulating blood volume (CCS) (for example, when taking diuretics in high doses), the recommended initial dose of Lozartan Canon is 25 mg (losartan in 25 mg tablets or 50 mg tablets with risk is possible). Patients with hepatic impairment (less than 9 on the Child-Pugh scale), hemodialysis, and patients older than 75 years are recommended a lower initial dose of the drug 25 mg (may use losartan in tablets 25 mg or in tablets 50 mg with a risk) 1 time per day.

Insufficient experience in the use of the drug in patients with severe hepatic insufficiency, so the drug is not recommended for this category of patients (see the section "Contraindications").

In patients with moderate renal dysfunction (KK 20-30 ml / min) dose adjustment is not required.

Side effects:

Classification of WHO frequency of development of side effects:

very often - ≥ 1/10 of appointments (> 10%)

often from ≥ 1/100 to <1/10 of appointments (> 1% and <10%)

infrequently - from ≥1 / 1000 to <1/100 of prescriptions (> 0.1% and <1%)

rarely from ≥1 / 10000 to <1/1000 appointments (> 0.01% and <0.1%)

very rarely - <1/10000 prescriptions (<0.01%)

the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Disorders from the blood and lymphatic system:

Rarely: anemia, thrombocytopenia.

Immune system disorders:

Rare: skin rash, urticaria, pruritus, angioedema (including swelling of the larynx and tongue), angioedema, allergic vasculitis, purpura Shenlyayna-G Enoch.

Impaired nervous system:

Often: dizziness, headache, sleep disturbance, insomnia. Uncommon: anxiety, sleepiness, memory disorders, peripheral neuropathy, paresthesia, hypoesthesia, migraine, tremor, ataxia, depression, syncope, acute cerebrovascular accident.

Disorders from the side of the organ of vision:

Infrequent: visual acuity, conjunctivitis.

Hearing disorders and labyrinthine disturbances:

Infrequent: ringing in the ears.

Disorders from the organ of taste:

Infrequently: a taste disorder.

Heart Disease:

Common: palpitations, tachycardia, bradycardia, arrhythmia.

Infrequently: angina.

Vascular disorders:

Infrequent: orthostatic hypotension (dose-dependent).

Disturbances from the respiratory system, chest and mediastinal organs:

Often: cough, infection of the upper respiratory tract (pharyngitis, rhinitis, sinusitis, bronchitis), swelling of the nasal mucosa.

Infrequently: dyspnea.

Disorders from the gastrointestinal tract:

Often: nausea, diarrhea, abdominal pain, dyspeptic disorders.

Infrequent: anorexia, dry mouth, vomiting, flatulence, constipation, gastritis.

Disorders from the liver and bile ducts:

Infrequent: a violation of the liver.

Rarely: hepatitis.

Disturbances from the skin and subcutaneous tissues:

Infrequent: dry skin, erythema, skin hyperemia, photosensitivity, increased sweating, alopecia.

Disturbances from the musculoskeletal and connective tissue:

Often: cramps in the muscles of the lower extremities, myalgia, pain in the back, chest, legs.

Infrequently: arthritis, arthralgia, fibromyalgia, rhabdomyolysis.

Disorders from the kidneys and urinary tract:

Infrequent: urinary tract infections, impaired renal function, mandatory urges to urinate, acute renal failure.

Violations of the genitals and breast:

Infrequent: decreased libido, impotence.

Common violations:

Often: asthenia, increased fatigue.

Laboratory and instrumental data:

Often: hyperkalemia.

Infrequent: moderate increase in the level of urea and serum creatinine, hypoglycemia, hyponatremia, hyperuricemia.

Very rarely: increased activity of "liver" enzymes, hyperbilirubinemia.

Overdose:

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

Treatment: forced diuresis, symptomatic therapy. Hemodialysis is not effective.

Interaction:

Can be used concomitantly with other antihypertensive agents.

There were no clinically significant drug interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin. Reportedly rifampicin and fluconazole reduce the concentration of the active metabolite in the blood plasma. The clinical significance of these interactions is still unknown.

As with the use of other agents that block the formation of angiotensin II and its effects, the concomitant use of potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium supplements and potassium-containing salts can lead to an increase in the potassium ion content in the serum.

Hypotensive drugs can increase the antihypertensive effectlosartan.

Also increase the antihypertensive effect of losartan may tricyclic antidepressants, antipsychotics, baclofen, amifostine, which reduce blood pressure as a major or side effect and may increase the risk of developing hypotension.

With the simultaneous use of angiotensin II receptor antagonists and non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of cyclooxygenase-2, acetylsalicylic acid as an anti-inflammatory agent), the antihypertensive effect of losartan may decrease. In patients with impaired renal function, simultaneous use of angiotensin II antagonists or diuretics and NSAIDs may cause further impairment of kidney function, including acute renal failure and an increase in serum potassium. This combination should be used with caution, especially in elderly patients.

With simultaneous use of lithium with ACE inhibitors, a reversible increase in serum lithium concentration and development of toxicity were recorded; in very rare cases, this was observed with angiotensin II receptor antagonists.Caution should be exercised when lithium is used simultaneously with losartan. If this combination is necessary, it is recommended to monitor the concentration of lithium in the blood serum.

Mutually enhances the effect of beta-blockers and sympatholytics; the combined use of losartan with diuretics causes an additive effect.

Double blockade of RAAS (eg, by combining an angiotensin II receptor antagonist with ACE inhibitors or aliskiren) in patients with an established diagnosis of atherosclerosis, heart failure, or diabetes with target organ damage is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia and impaired function kidneys (including the development of acute renal failure) compared with the use of a one-component blockade of the RAAS. The question of using the double blockade of RAAS should be solved in each case individually and with careful monitoring of blood pressure, water-electrolyte balance of blood and kidney function.

Special instructions:

In patients with reduced BCC (eg, receiving high doses of diuretics) symptomatic arterial hypotension may occur,therefore, before the start of treatment, it is necessary to replace BCC or begin treatment with Lozartan Canon at a lower dose.

In patients with cirrhosis of the liver, the concentration of losartan in the blood plasma is significantly increased, and therefore, in the presence of liver diseases in the history, it should be prescribed in lower doses.

During the treatment should be regularly monitored potassium in the blood plasma and creatinine clearance, especially in elderly patients, patients with impaired renal function, patients with type 2 diabetes mellitus complicated by nephropathy; and especially carefully monitor these indicators in patients with heart failure with concomitant renal dysfunction.

Drugs that affect RAAS can increase the concentration of urea in the blood and serum creatinine in patients with bilateral renal stenosis or stenosis of the artery of a single kidney.

The experience of losartan in patients after kidney transplantation is not.

In patients with severe chronic heart failure, 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 with losartan in patients with heart failure with concomitant severe renal failure, in patients with severe chronic heart failure (NYHA functional class IV), in patients with heart failure with life-threatening arrhythmias. In these groups with caution should be used drug Lozartan Canon with beta-blockers.

Like all drugs that have a vasodilating effect, the drug Losartan Canon should be administered with caution to patients with aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

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

Caution should be exercised when administering Lozartan Canon to patients who had a history of anginaevrotic edema, including when taking other medications, including ACE inhibitors.

Patients with primary hyperaldosteronism usually do not respond to antihypertensive agents acting through inhibition of the renin-angiotensin system. Therefore, it is not recommended to use the drug Losartan Canon for the treatment of such patients.

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

There have been no studies to evaluate the effect of the drug on the management of vehicles and mechanisms.

It should be borne in mind the possibility of drowsiness and dizziness, so you need to be careful when performing work that requires increased attention, especially at the beginning of treatment, with an increase in the dose of the drug and in the management of vehicles.

Form release / dosage:Tablets, film-coated, 50 mg and 100 mg.

Packaging:

By 7, 10, 28 or 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

1, 2, 4 contour packs of 7 tablets or 1, 3, 6 contour packs of 10 tablets or 1, 2 contour packs of 28 tablets or 1, 2, 3 contourcell packs of 30 tablets together with instructions for use put in a pack of cardboard.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002356

Date of registration:03.02.2014 / 17.07.2017

Expiration Date:03.02.2019

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Information update date: & nbsp04.04.2018

Illustrated instructions

Instructions

Losartan Canon (Losartan Canon)