Composition, form of production and packaging
Tablets covered with a film coat of white or almost white color, round, biconcave; on a cross section - almost white.
1 tab.
Losartan potassium 50 mg
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.
The composition of the film shell: opadray white - 4 mg (hypromellose (hydroxypropylmethylcellulose) - 1.35 mg, giprolose (hydroxypropyl cellulose) - 1.35 mg, talc 0.8 mg, titanium dioxide 0.5 mg).
7 pcs. - packings of cellular contour (1) - packs cardboard.
7 pcs. - packings cellular planimetric (2) - packs cardboard.
7 pcs. - packings cellular planimetric (4) - packs cardboard.
10 pieces. - packings of cellular contour (1) - packs cardboard.
10 pieces. - packings cellular planimetric (3) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
28 pcs. - packings of cellular contour (1) - packs cardboard.
28 pcs. - packings cellular planimetric (2) - packs cardboard.
30 pcs. - packings of cellular contour (1) - packs cardboard.
30 pcs. - packings cellular planimetric (2) - packs cardboard.
30 pcs. - packings cellular planimetric (3) - packs cardboard.
The tablets covered with a film membrane of white or almost white color, round, biconcave; on a cross section - almost white.
1 tab.
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.
The composition of the film shell: opadray white - 8 mg (hypromellose (hydroxypropylmethylcellulose) - 2.7 mg, giprolose (hydroxypropyl cellulose) - 2.7 mg, talc - 1.6 mg, titanium dioxide - 1 mg).
7 pcs. - packings of cellular contour (1) - packs cardboard.
7 pcs. - packings cellular planimetric (2) - packs cardboard.
7 pcs. - packings cellular planimetric (4) - packs cardboard.
10 pieces. - packings of cellular contour (1) - packs cardboard.
10 pieces. - packings cellular planimetric (3) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
28 pcs. - packings of cellular contour (1) - packs cardboard.
28 pcs. - packings cellular planimetric (2) - packs cardboard.
30 pcs. - packings of cellular contour (1) - packs cardboard.
30 pcs. - packings cellular planimetric (2) - packs cardboard.
30 pcs. - packings cellular planimetric (3) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antihypertensive drug. Selective antagonist of angiotensin II receptors (type AT 1 ). Angiotensin II is a potent vasoconstrictor, the main active hormone of RAAS, and the decisive pathophysiological link in the development of hypertension. 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 AT 1 -receptors 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. In addition, losartan does not inhibit ACE, which is responsible for the destruction of bradykinin. Consequently, effects not directly associated with blockade of AT 1 -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 OPSS, the concentration in the blood of norepinephrine and aldosterone, blood pressure, pressure in a small circle of 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 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 gradually decreases within 24 hours. In the course of treatment, antihypertensive activity and a decrease in plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, which indicates an effective blockade of angiotensin II receptors. However, after the replacement of losartan, the plasma renin activity and the angiotensin II level decreased to the baseline values ​​observed before the drug was administered after 3 days.
Both losartan and its active metabolite have a higher affinity for AT 1 receptors than for AT 2 receptors. The active metabolite is 10-40 times more active than losartan.
PHARMACOKINETICS
Suction
When ingested, losartan is well absorbed from the digestive tract and at the same time it undergoes metabolism at the "first passage" through the liver by carboxylation with the participation of the CYP2C9 isoenzyme with the formation of an active metabolite.
Systemic bioavailability of losartan is approximately 33%. C max losartan and its active metabolite are reached in the blood serum approximately after 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%. V d of losartan is 34 liters. Losartan practically does not penetrate the BBB.
Losartan and its active metabolite demonstrate linear pharmacokinetics when administered in doses up to 200 mg. When the dosage regimen is 100 mg 1 time / day, there is no significant cumulation in the plasma of either losartan or its active metabolite.
Metabolism
Approximately 14% of the dose of losartan, administered intravenously or intravenously, is converted to its active metabolite. After ingestion or intravenous administration of radiolabeled 14 C labeled losartan, the radioactivity of the 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, incl. two basic, resulting from the hydroxylation of the butyl side chain, and one secondary is 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.
After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite T 1/2 of approximately 2 and 6-9 hours, respectively. The excretion of losartan and its metabolites occurs through the intestine with bile and kidneys. After ingestion of radiolabeled 14 C of losartan, about 35% of radioactivity is found in urine and 58% in feces. After intravenous administration of radiolabeled 14 C losartan, approximately 43% of radioactivity is detected in urine and 50% in feces.
Pharmacokinetics in specific patient groups
The concentrations 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.
Values ​​of 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.
When losartan was administered orally to patients with mild and moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in blood plasma were 5 and 1.7 times higher, respectively, than in young healthy male volunteers.
Plasma concentrations of losartan in patients with QC above 10 ml / min did not differ from those in patients with unchanged renal function. When compared with AUC in patients with normal renal function, the value of 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. Lozartan and its active metabolite are not excreted by hemodialysis.
INDICATIONS
- arterial hypertension;
- reduced 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 hypercreatininemia, the incidence of the terminal stage of chronic renal failure requiring dialysis or kidney transplantation, mortality rates, and a decrease in proteinuria.
DOSING MODE
The drug is taken orally, 1 time / day, in the morning (preferably at the same time), regardless of food intake. Tablets should be swallowed, not liquid and squeezed with water.
With 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 / day or 50 mg 2 times / day .
When the drug is prescribed to reduce the risk of developing cardiovascular diseases and mortality in patients with hypertension and left ventricular hypertrophy, theinitial dose of the drug is 50 mg 1 time / day. In the future, hydrochlorothiazide can be added at low doses or the dose of Lozartan Canon can be increased to a maximum of 100 mg in 1 or 2 doses, taking into account the decrease in blood pressure.
In cases of congestive heart failure, the initial dose 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.Рµ. 12.5 mg / day, 25 mg / day, 50 mg / day to an average maintenance dose of 50 mg / day.
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 blood pressure reduction) in 1 or in 2 doses.
In patients with reduced BCC (for example, when taking diuretics in high doses) the recommended initial dose of Lozartan Kanon is 25 mg (losartan in 25 mg tablets or 50 mg tablets with risk may be used).
In elderly patients with renal insufficiency, dose adjustment is not required.
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 / day.
There is insufficient experience in using the drug in patients with severe hepatic insufficiency , therefore the drug is not recommended for this category of patients.
In patients with moderate renal dysfunction (KK 20-30 ml / min) dose adjustment is not required.
SIDE EFFECT
Classification of WHO frequency of development of side effects: very often -? 1/10 appointments (> 10%), often - from? 1/100 to <1/10 appointments (> 1% and <10%), infrequently from? 1 / 1000 to <1/100 of prescriptions (> 0.1% and <1%), rarely from? 1/10 000 to <1/1000 appointments (> 0.01% and <0.1%), very rarely - <1/10 000 prescriptions (<0.01%), the frequency is unknown - according to available data, it is not possible to establish the frequency of occurrence.
From the hemopoietic system: rarely - anemia, thrombocytopenia.
From the nervous system: often - dizziness, headache, sleep disturbance, insomnia; infrequently - anxiety, drowsiness, memory disorder, peripheral neuropathy, paresthesia, hypoesthesia, migraine, tremor, ataxia, depression, syncope, acute impairment of cerebral circulation.
From the side of the organ of vision: infrequently - a violation of visual acuity, conjunctivitis.
From the side of the organ of hearing: infrequent - ringing in the ears.
From the cardiovascular system: often - a feeling of palpitations, tachycardia, bradycardia, arrhythmia; infrequently - stenocardia, orthostatic hypotension (dose-dependent).
On the part of the respiratory system: often - cough, infections of the upper respiratory tract (pharyngitis, rhinitis, sinusitis, bronchitis), swelling of the nasal mucosa;infrequently - dyspnoea.
On the part of the digestive system: often - nausea, diarrhea, abdominal pain, dyspeptic disorders; infrequent - a violation of taste, anorexia, dry mouth, vomiting, flatulence, constipation, gastritis, impaired liver function; rarely - hepatitis.
On the part of the urinary system: infrequently - urinary tract infections, renal dysfunction, mandatory urges to urinate, acute renal failure.
From the genitals and the breast: infrequently - decreased libido, impotence.
From the skin and subcutaneous tissues: infrequently - dry skin, erythema, skin hyperemia, photosensitivity, increased sweating, alopecia.
From the musculoskeletal system: often - convulsions in the muscles of the lower extremities, myalgia, pain in the back, chest, legs; infrequently - arthritis, arthralgia, fibromyalgia, rhabdomyolysis.
Allergic reactions: rarely - skin rash, hives, itching, angioedema (including laryngeal edema and tongue), Quincke's edema, allergic vasculitis, purple Shenlaine-Genocha.
From laboratory and instrumental data: often - hyperkalemia; infrequent - moderate increase in the concentration of urea and serum creatinine, hypoglycemia, hyponatremia, hyperuricemia; very rarely - increased activity of hepatic enzymes, hyperbilirubinemia.
Other: often - asthenia, increased fatigue.
CONTRAINDICATIONS
- arterial hypotension;
- hepatic insufficiency of severe degree (more than 9 points on the Child-Pugh scale);
- primary hyperaldosteronism;
- simultaneous use with aliskiren in patients with diabetes mellitus and patients with renal failure (CC less than 60 ml / min);
- Pregnancy;
- the period of lactation (breastfeeding);
- age under 18 years (effectiveness and safety not established);
- Hypersensitivity to the active substance or to other components of the drug.
With caution should prescribe the drug in violation of water-electrolyte balance (hyponatremia, hypochloraemic alkalosis, hypomagnesemia, hypokalemia, hyperkalemia); decrease in 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; IHD; cerebrovascular diseases; Hepatic insufficiency (less than 9 on the Child-Pugh scale); an angioneurotic edema in the anamnesis.
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 and III trimesters, since renal perfusion in the fetus, depending on 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 1 in 1,000 women), when the use of all other antihypertensive drugs is not possible, administration of the drug under the close supervision of the doctor, including a weekly ultrasound of the fetus, is permitted. 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 and III trimesters of pregnancy can lead to impaired development and / or death of the fetus, 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 is excreted in breast milk, so Lozartan Canon is contraindicated during breastfeeding. If it is necessary to use the drug, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution should be given to the drug for kidney failure; condition after kidney transplantation (no experience of application).
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be given to patients with liver failure (less than 9 on the Child-Pugh scale).
The use of the drug in patients with severe hepatic insufficiency is contraindicated (more than 9 on the Child-Pugh scale).
APPLICATION FOR CHILDREN
The use of the drug in children and adolescents under the age of 18 is contraindicated.
APPLICATION IN ELDERLY PATIENTS
In elderly patients with renal insufficiency, dose adjustment is not required.
SPECIAL INSTRUCTIONS
In patients with reduced BCC (eg, receiving diuretics in high doses), symptomatic arterial hypotension may occur, so it is necessary to replace BCC or begin treatment with Lozartan Canon at a lower dose before starting treatment.
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 period, the potassium content in the blood plasma and QC should be regularly monitored, especially in elderly patients, patients with renal dysfunction, patients with type 1 diabetes mellitus complicated by nephropathy; 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, the use of drugs that affect RAAS can lead to severe arterial hypotension and acute renal failure. There are some reports about the development of oliguria and / or progressive azotemia and acute renal failure, including fatal.
There is not enough experience with losartan in heart failure patients with concomitant severe renal impairment, in patients with severe chronic heart failure (IV functional class NYHA classification), in patients with heart failure, life-threatening arrhythmias. In these groups, with the caution should be used drug Losartan Canon with beta-blockers.
As with all drugs with vasodilating action, drug Losartan Canon should be used with caution in patients with aortic or mitral stenosis, obstructive or hypertrophic cardiomyopathy.
In patients with ischemic cerebrovascular disease character of an excessive fall in blood pressure can lead to stroke. Recommended medical supervision during dose titration.
Caution must be exercised when administering the drug Losartan Canon patients with a history of which instructions are transferred to angioedema, including when taking other drugs, including ACE inhibitors.
Patients with primary hyperaldosteronism generally do not respond to antihypertensive agents, acting via inhibition of the RAAS. Therefore it is not recommended to use Losartan Canon drug for treatment of such patients.
Impact on the ability to drive vehicles and manage mechanisms
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 use caution when performing tasks that require special attention, especially at the beginning of treatment, at higher doses and when driving.
OVERDOSE
Symptoms: excessive lowering of blood pressure, tachycardia. Bradycardia can occur due to parasympathetic (vagal) stimulation.
Treatment: forced diuresis, symptomatic therapy. Hemodialysis is not effective.
DRUG INTERACTION
Losartan may be used concomitantly with other antihypertensive agents.
There was no any clinically significant drug interaction of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin.
According to rifampicin and fluconazole reduces the concentration of the active metabolite in the blood plasma. The clinical significance of this interaction is still unknown.
As with other means of blocking the formation of angiotensin II and its effects, concomitant administration of potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium supplements and salts containing potassium, may increase the content of potassium ions in serum.
Antihypertensives may enhance the hypotensive effect of losartan.
Tricyclic antidepressants, antipsychotics, baclofen, amifostine, which lower blood pressure in a main or side affect, may enhance the hypotensive effect of losartan and increase the risk of hypotension.
With simultaneous use of the angiotensin II receptor antagonists and NSAIDs (including selective COX-2 inhibitors, acetylsalicylic acid as an anti-inflammatory agent) can be reduced hypotensive effect of losartan. Patients with impaired renal function simultaneous use of the angiotensin II antagonists or diuretics and NSAIDs can cause further deterioration of renal function, including acute renal failure and increase in potassium in serum. This combination should be used with caution, especially in elderly patients.
With simultaneous use of lithium reversible increases lithium concentrations have been reported with ACE inhibitors in serum and the development of toxicity; In very rare cases, this occurred when using angiotensin II receptor antagonists. With simultaneous use of lithium losartan with caution. If the combination is necessary, it is recommended to monitor the concentration of lithium in blood serum.
Mutually reinforces the effect of beta-blockers and sympatholytic; the combined use of losartan with a diuretic causes an additive effect.
Dual blockade of the RAAS (e.g., by combining an angiotensin II receptor antagonist with an ACE inhibitor or aliskiren) in patients with an established diagnosis of atherosclerosis, heart failure or diabetes with lesions target organs associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including the development of acute renal failure) as compared to using a single-component blockade of the RAAS. The question of the application of double RAAS blockade must be resolved in each case individually and with careful monitoring of blood pressure, fluid and electrolyte balance of the blood and kidney function.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, dry, dark place at a temperature not higher than 25 В° C. Shelf life - 2 years.
