Instructions Closart film-coated tablets 100 mg No. 30
Composition
active ingredient: losartan;
1 tablet contains losartan potassium 25 mg, 50 mg or 100 mg;
excipients: microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry O3B 52014 yellow*.
*Opadry O3B 52014 yellow: iron oxide yellow (E 172), quinoline yellow (E 104), hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex tablets, coated with a yellow film coating.
Pharmacotherapeutic group
Simple angiotensin II antagonist drugs.
ATX code C09C A01.
Pharmacological properties
Pharmacodynamics.
Losartan potassium is an angiotensin II (type AT1) receptor antagonist. Angiotensin II, formed from angiotensin I by the angiotensin-converting enzyme (ACE, kininase II), is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component of the pathophysiological mechanisms of arterial hypertension. Angiotensin II also binds to the AT1 receptor, which is found in many tissues (vascular smooth muscle, adrenal glands, kidneys, and heart), determining a number of important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.
Losartan and its active carboxylic acid metabolite block all physiologically relevant effects of angiotensin II, regardless of the source or route of synthesis.
Losartan selectively binds to the AT1 receptor and does not bind to or block other hormone receptors or ion channels.
Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that catalyzes the degradation of bradykinin. As a result, effects not directly related to AT1 receptor blockade, such as potentiation of bradykinin-mediated effects, are not associated with the use of losartan.
During the use of losartan, the elimination of the negative feedback loop of angiotensin II on renin secretion leads to an increase in plasma renin activity. This increase in activity leads to an increase in plasma angiotensin II. Although this increase occurs, antihypertensive activity and suppression of plasma aldosterone concentrations are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and angiotensin II levels return to baseline within 3 days.
Both losartan and its major metabolite have a higher affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10-40 times more active than losartan.
Pharmacokinetics.
After oral administration, losartan is well absorbed and undergoes first-pass metabolism. The systemic bioavailability of the drug is approximately 33%. Almost 14% of an oral dose of losartan is converted to the active carboxyl metabolite. The maximum concentration of losartan and its active metabolite is recorded after 1 hour and 3-4 hours, respectively. Losartan and the active metabolite are intensively bound to plasma proteins, mainly albumin. The half-life of losartan is 2 hours, and that of the active metabolite is 6-9 hours. The pharmacokinetics of losartan and the active metabolite are linear for oral doses of losartan up to 200 mg and do not change with time. Losartan and the active metabolite do not accumulate in plasma with repeated once-daily dosing. Approximately 4% of the dose is excreted unchanged in the urine and almost 6% is excreted as the active metabolite. Biliary excretion of the drug accounts for some of the elimination of losartan and its active metabolite - approximately 35% of the dose is excreted in the urine and almost 58% in the feces.
Elderly patients.
No significant changes in pharmacokinetic characteristics were found in elderly patients with arterial hypertension compared to young patients.
Sex.
Plasma concentrations of losartan in women with arterial hypertension were 2 times higher than those in men. No gender dependence of the concentration of the active metabolite was found.
Liver and kidney dysfunction.
Plasma concentrations of losartan and its active metabolite in patients with impaired liver function are 1.7-5 times higher than in patients with normal liver function.
Plasma concentrations of losartan in patients with creatinine clearance above 10 ml/min did not differ from those in healthy subjects. The area under the concentration curve (AUC) in patients with severe renal impairment was 2 times higher than the AUC of losartan in patients with normal renal function. Plasma concentrations of the active metabolite of losartan remained unchanged. Losartan and its active metabolite cannot be removed by hemodialysis.
The active metabolite of losartan is formed in patients of all age groups. The pharmacokinetics of losartan after oral administration are approximately similar in neonates and children aged 2 years and older, preschool children, school-age children and adolescents. The pharmacokinetics of the metabolite are more age-dependent, especially when comparing preschool children and adolescents. Exposure in neonates and children under 2 years of age is relatively high.
Indication
Treatment of essential hypertension in adults and children aged 6 years and over. Treatment of kidney disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day - as part of antihypertensive therapy. Treatment of chronic heart failure (in patients over 60 years of age) in cases where the use of angiotensin-converting enzyme (ACE) inhibitors is considered impossible due to intolerance (especially in case of cough) or in the presence of contraindications. Closarta is not recommended for patients with heart failure whose condition is stable while taking ACE inhibitors. The patient's left ventricular ejection fraction should be ≤ 40%, the condition should be clinically stable, and the patient should also adhere to the established treatment regimen for chronic heart failure. Reducing the risk of stroke in adult patients with arterial hypertension and left ventricular hypertrophy, confirmed by ECG.
Contraindication
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe hepatic impairment. Pregnant women or women planning to become pregnant (see section "Use during pregnancy and lactation").
The concomitant use of losartan and aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) is contraindicated (see sections “Method of administration and dosage”, “Special precautions for use”, “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Other antihypertensive agents may enhance the hypotensive effect of losartan. Concomitant use with other drugs that can induce such a side effect as arterial hypotension (tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of arterial hypotension.
Losartan is primarily metabolized by cytochrome P450 (CYP) 2C9 to the active metabolite, the carboxylic acid. Fluconazole has been shown to reduce exposure to the active metabolite by approximately 50%, and concomitant treatment with losartan and rifampicin (an inducer of metabolic enzymes) resulted in a 40% decrease in plasma concentrations of the active metabolite. The clinical significance of this effect is unknown. There is no difference in exposure when losartan is coadministered with fluvastatin (a weak inhibitor of CYP2C9).
As with other drugs that block angiotensin II or its effects, concomitant use of drugs that retain potassium in the body (e.g., potassium-sparing diuretics: spironolactone, triamterene, amiloride) or may increase potassium levels (e.g., heparin), potassium supplements or salt substitutes containing potassium, may lead to increases in serum potassium. Concomitant use of such drugs is not recommended.
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium with ACE inhibitors. Concomitant use of lithium and losartan should be undertaken with caution. If the combination is considered necessary, monitoring of serum lithium levels is recommended during treatment.
Dual blockade (e.g. by adding an ACE inhibitor or aliskiren to angiotensin II receptor antagonists) should be limited to individually defined cases with careful monitoring of blood pressure, renal function and electrolytes. In individual studies, dual blockade of the renin-angiotensin-aldosterone system has been shown to be associated with a higher incidence of hypotension, syncope, hyperkalaemia and changes in renal function (including acute renal failure) in patients with established atherosclerosis, heart failure or diabetes with organ damage, compared with the use of a single agent acting on the renin-angiotensin-aldosterone system. The concomitant administration of aliskiren with losartan is not recommended in patients with diabetes mellitus or in patients with renal insufficiency (GFR <60 ml/min) (see section 4.3).
Application features
Pregnancy.
Angiotensin II receptor antagonists are contraindicated during pregnancy. Patients receiving angiotensin II receptor antagonists and planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Hypersensitivity.
Angioedema. While taking the drug, patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be constantly monitored for their general condition.
Arterial hypotension and water and electrolyte imbalance.
Symptomatic hypotension, especially after the first dose or dose increase, may occur in patients with reduced intravascular volume or sodium depletion caused by the use of potent diuretics, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected before starting treatment with losartan or the initial dose should be reduced. The same recommendations apply to children aged 6 years and older.
Electrolyte imbalance.
Electrolyte imbalances are common in patients with renal impairment (with or without diabetes mellitus) and should be considered. Plasma potassium concentrations (possibility of hyperkalemia) and creatinine clearance should be closely monitored, especially in patients with heart failure and creatinine clearance of 30-50 ml/min.
The concomitant use of losartan and potassium-sparing diuretics, potassium supplements, and salt substitutes containing potassium is not recommended.
Liver dysfunction.
Given the pharmacokinetic data indicating a significant increase in plasma concentrations of losartan in patients with cirrhosis, dose reduction should be considered in patients with a history of hepatic impairment. There is no experience in patients with severe hepatic impairment.
The drug is not recommended for use in children with liver dysfunction.
Kidney dysfunction.
Changes in renal function, including renal failure, have been reported, which have been associated with inhibition of the renin-angiotensin system (especially in patients whose renal function depends on the renin-angiotensin-aldosterone system, i.e. patients with severe cardiac dysfunction or pre-existing renal dysfunction).
Drugs that affect the renin-angiotensin-aldosterone system may cause increases in blood urea and serum creatinine in patients with bilateral renal artery stenosis, renal artery stenosis or stenosis of the artery to a solitary kidney. These changes in renal function may be reversible after discontinuation of therapy. Closart ® should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Use in children with renal impairment.
The drug is not recommended for use in children with a glomerular filtration rate < 30 ml/min/1.73 m2, as there are no relevant data on use.
During the period of use of Closart®, renal function should be regularly checked, as its deterioration is possible. This is especially true when Closart® is used in the presence of other pathological conditions (fever, dehydration) that may affect renal function.
The simultaneous use of Closart and ACE inhibitors worsens kidney function, so this combination is not recommended.
Kidney transplantation.
There is no experience regarding the safety of losartan in patients who have recently undergone kidney transplantation.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism generally do not respond to drugs that inhibit the renin-angiotensin system. Therefore, Closart® is not recommended for this group of patients.
As with other antihypertensive drugs, excessive reduction in blood pressure in patients with ischemic coronary artery disease and cerebrovascular disease may lead to the development of myocardial infarction or stroke.
Heart failure.
As with other drugs that affect the renin-angiotensin-aldosterone system, there is a risk of severe hypotension and (often acute) renal impairment in patients with heart failure with/without renal impairment.
There is insufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV), or in patients with heart failure and symptomatic life-threatening cardiac arrhythmias. Therefore, losartan should be used with caution in this group of patients. Caution should be exercised when using losartan and β-blockers concomitantly.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.
As with other vasodilators, Closart® should be administered with extreme caution to patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Other caveats.
As has been shown for angiotensin-converting enzyme inhibitors, losartan and other angiotensin antagonists are less effective in black patients than in non-black patients, possibly because of lower renin activity in black hypertensive patients.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Hypotension, syncope, stroke, hyperkalemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially when combined with medicinal products that affect this system (see section 4.5).
Therefore, dual blockade of the renin-angiotensin-aldosterone system by combining an angiotensin II receptor blocker (ARB) with angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren is not recommended.
The combination with aliskiren is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR <60 mL/min/1.73 m2).
Use during pregnancy or breastfeeding
Pregnancy.
The drug is contraindicated for use in pregnant women or women planning to become pregnant (see sections "Contraindications" and "Special instructions for use"). If pregnancy is confirmed during treatment with this drug, its use should be immediately discontinued and replaced with another drug approved for use in pregnant women.
It is known that the use of ARAII during the II and III trimesters induces fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).
If AIIRAs were used during the second trimester of pregnancy, an ultrasound examination is recommended to check kidney function and the condition of the skull bones.
Newborns whose mothers have taken ARBs should be frequently monitored for the development of hypotension.
Breastfeeding: As no information is available regarding the use of losartan during breast-feeding, this drug is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially during the neonatal period or when the infant is premature.
The ability to influence the reaction speed when driving or working with other mechanisms
Data on the effect of losartan on the ability to drive and use machines are limited. The possibility of developing side effects such as dizziness and drowsiness should be taken into account, especially at the beginning of treatment and when the dose of the drug is increased.
Method of administration and doses
Take the tablets regardless of meals, with 1 glass of water.
Arterial hypertension.
For most patients, the usual starting and maintenance dose of Closartan is 50 mg once daily. The maximum antihypertensive effect is achieved 3–6 weeks after initiation of treatment. Some patients may benefit from increasing the dose to 100 mg once daily (in the morning).
Closart® can be used in combination with other antihypertensive drugs, especially with diuretics (e.g. hydrochlorothiazide).
Patients with hypertension, type 2 diabetes mellitus and proteinuria
( ≥ 0.5 g/day).
The usual starting dose of Closartan is 50 mg once daily. The dose may be increased to
100 mg once daily depending on blood pressure readings 1 month after initiation of treatment. Closart® can be used with other antihypertensive agents (diuretics, calcium channel blockers, α- or β-receptor blockers, centrally acting agents), as well as with insulin and other hypoglycemic agents (e.g. sulfonylureas, glitazones and glucosidase inhibitors).
The usual starting dose of losartan for patients with chronic heart failure is 12.5 mg once daily. The dose is usually titrated at weekly intervals (i.e.
12.5 mg per day, 25 mg per day, 50 mg per day) to the usual maintenance dose of 50 mg (1 tablet of Closartan 50 mg) once a day depending on individual tolerability.
Reduction in the risk of stroke in patients with arterial hypertension and left ventricular hypertrophy, as documented by ECG.
The usual starting dose is 50 mg once daily. Depending on the response to blood pressure, it may be necessary to administer low doses of hydrochlorothiazide and/or increase the dose of losartan to 100 mg once daily.
Certain groups of patients.
Use in patients with reduced circulating blood volume.
For patients with reduced circulating blood volume (e.g. due to the use of high doses of diuretics), therapy should be initiated with a dose of 25 mg once daily.
Use in patients with renal failure and patients undergoing hemodialysis.
When prescribing Closart to patients with impaired renal function, as well as patients undergoing hemodialysis, initial dose adjustment is not required.
Use in patients with a history of liver dysfunction.
For patients with a history of hepatic impairment, a lower dose should be considered. There is no experience in treating patients with severe hepatic impairment, therefore Closart ® is contraindicated in this group of patients.
Use in children aged 6 years and over.
For children who can swallow tablets and whose body weight is more than 20 kg and less than 50 kg, the recommended dose is 25 mg once a day. In exceptional cases, the dose may be increased to a maximum of 50 mg once a day. The dose should be adjusted depending on changes in blood pressure.
In patients weighing more than 50 kg, the recommended dose is 50 mg once daily. In exceptional cases, the dose may be increased to a maximum of 100 mg once daily. Doses exceeding 1.4 mg/kg (or more than 100 mg) per day have not been studied in children.
Closart® is not recommended for use in children with impaired liver function.
Closart® is also not recommended for use in children with a glomerular filtration rate < 30 ml/min/1.73 m2, as there are no relevant data on such use.
Use in patients over 75 years of age.
Therapy should be initiated at a dose of 25 mg once daily. Dose adjustment is usually not required.
Children.
The safety and effectiveness of Closart in children under 6 years of age have not been established.
Overdose
Symptoms of overdose.
Data on overdose with losartan are limited. The most likely manifestations of overdose are hypotension and tachycardia; bradycardia may be due to parasympathetic (vagal) stimulation.
Treatment. Treatment depends on the length of time since taking the drug, as well as on the nature and severity of the symptoms. The priority should be to stabilize the function of the cardiovascular system. After oral administration of losartan, the use of activated charcoal in an appropriate dose is indicated. Later, the main vital signs of the body should be monitored frequently and adjusted if necessary. Losartan and its active metabolites are not removed by hemodialysis.
Adverse reactions
From the nervous system: dizziness, drowsiness, headache, insomnia, muscle cramps, paresthesia, stroke, migraine, dysgeusia.
From the side of the organs of hearing and labyrinth: vertigo, tinnitus.
Psychiatric: depression.
Cardiac: palpitations, syncope, angina pectoris, tachycardia, atrial fibrillation.
Vascular disorders: symptomatic hypotension (especially in patients with intravascular dehydration, e.g. patients with severe heart failure or treated with high doses of diuretics), dose-dependent orthostatic effect.
On the part of the digestive tract: abdominal pain, dyspepsia, constipation, diarrhea, pancreatitis, nausea, vomiting.
From the hepatobiliary system: hepatitis, liver dysfunction.
Respiratory system: cough, dyspnea, rhinitis, sinusitis, pharyngitis, upper respiratory tract infection.
Renal and urinary tract disorders: changes in renal function, including renal failure in patients at risk (such changes in renal function may be reversible upon discontinuation of therapy), urinary tract infections.
From the blood and lymphatic system: anemia, thrombocytopenia.
General condition and disorders related to the method of administration of the drug: asthenia/weakness, malaise, edema, flu-like symptoms.
Skin and subcutaneous tissue disorders: urticaria, itching, rash, photosensitivity, erythroderma.
Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, rhabdomyolysis.
Reproductive system and breast disorders: erectile dysfunction/impotence.
Laboratory indicators: hypoglycemia, hyperkalemia, hyponatremia, increased ALT levels, increased blood urea levels, serum creatinine.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 ºС in the original packaging.
Keep out of reach of children.
Packaging
Tablets of 25 mg, 50 mg.
14 tablets in a blister; 1, 2 or 6 blisters in a cardboard box.
Tablets of 100 mg.
14 tablets in a blister; 1, 2 or 6 blisters in a cardboard box.
10 tablets in a blister; 3 or 10 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"KUSUM FARM" LLC.
Location of the manufacturer and its business address
Ukraine, 40020, Sumy, Skryabina St., 54.
