for medical use
Active substance: losartan.
1 film c tablet contains Losartan potassium 25 mg, 50 mg or 100 mg
Excipients: Microcrystalline cellulose, Sodium сroscarmellose, Magnesium stearate, Colloidal silicon dioxide anhydrous, Opadry О3В 52014 yellow.
* Opadry О3В 52014 yellow: yellow iron oxide (E 172), quinoline yellow (E 104), hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide (E 171).
Pharmaceutical Form. Film coated tablets.
General physicochemical properties:yellow film coated round biconvex tablets.
Angiotensin II antagonists, plain.
Code ATC: C09C A01.
Losartan potassium is an angiotensin II (type АТ1) receptors antagonist. Angiotensin II, which is formed from angiotensin I during reaction involving the angiotensin-converting enzyme (ACE, kininase II), is a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II also binds to the AT1 receptor found in many tissues (vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation.
Losartan and its active metabolite carboxylic acid block all physiologically significant effects of angiotensin II, regardless of the source or route of synthesis.
Losartan selectively binds to AT1 receptor; it doesn’t bind or block other hormone receptors or ion channels.
Furthermore Losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, the effects which are not directly related to AT1 receptor blockade such as increase of effects mediated by bradykinin are not associated with the use of losartan.
During administration of losartan, removal of angiotensin-II negative feedback on renin secretion leads to increased plasma renin activity. Such increase leads to increases in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin-II receptor blockade. After discontinuation of losartan, plasma renin activity and angiotensin II values within three days come back to the baseline values.
Both losartan and its principal active metabolite have a far greater affinity for the AT1-receptor than for the AT2-receptor. The active metabolite is 10- to 40- times more active than losartan.
Following oral administration, losartan is well absorbed and undergoes first-pass metabolism. The systemic bioavailability of losartan tablets is approximately 33%. Almost 14% of the oral dose of losartan is converted to the active carboxyl metabolite. Maximal concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. Both losartan and its active metabolite are intensively bound to plasma proteins, primarily albumin. The half-life of losartan is 2 hours, of its active metabolite – 6-9 hours. The pharmacokinetics of losartan and its active metabolite is linear for oral doses of losartan up to 200 mg, and is not changed with time. Neither losartan nor its active metabolite accumulates in blood plasma in case of repeated administration once daily. About 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its active metabolite – about 35% of the dose is recovered in the urine, and about 58% - in the faeces.
No significant changes in pharmacokinetic characteristics have been found in elderly hypertensive patients compared to the young patients.
In female hypertensive patients the plasma levels of losartan were twice as high as in male hypertensive patients. The concentration of active metabolite did not depend on gender.
Liver and kidney dysfunction.
In patients with liver dysfunction plasma levels of losartan and its active metabolite are 1.7-5 times higher than in patients with intact liver function.
Plasma concentrations of losartan were not altered in patients with creatinine clearance above 10 ml/min. Compared to patients with normal renal function, the area under the concentration curve (AUC) for losartan is about 2 times higher in patients with severe renal impairment. Along with this, the plasma concentrations of the active metabolite are not altered. Neither losartan nor the active metabolite can be removed by haemodialysis.
Pharmacokinetics in paediatric patients.
The active metabolite is formed from losartan in all age groups. The pharmacokinetic parameters of losartan following oral administration are roughly similar in infants and children aged over 2 years, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups, especially when comparing preschool children with adolescents. Exposure in infants and children aged over 2 years is comparatively high.
Treatment of essential hypertension in adults and in children over 6 years old.
Treatment of kidney disease in adult patients with hypertension and type II diabetes mellitus with proteinuria ≥ 0.5 g/day – as a part of antihypertensive therapy.
Treatment of chronic heart failure (in patients aged over 60 years) in cases where the use of inhibitors of angiotensin-converting enzyme (ACE) is considered to be impossible due to intolerance (especially when coughing) or in the presence of contraindications. In patients with heart failure whose condition while taking ACE inhibitors is stable, prescribing Klosart is not advisable. The patient’s left ventricular ejection fraction should be ≤ 40%, the condition should be clinically stable, the patient also should follow the established treatment regimen for chronic heart failure.
Reducing the risk of stroke in adults with hypertension and left ventricular hypertrophy, as confirmed by ECG.
Hypersensitivity to the active substance or to any excipient contained in the preparation.
Severe liver dysfunction.
Interaction with other medicinal products and other forms of interaction.
Other antihypertensive agents may increase the hypotensive action of losartan. Concomitant use with the drugs that lower blood pressure, as main or side-effect may increase the risk of hypotension (tricyclic antidepressants, antipsychotics, baclofen, amifostine).
Losartan is predominantly metabolised by cytochrome P450 (CYP) 2C9 to the active carboxy-acid metabolite. It was found that fluconazole decreases the exposure to the active metabolite by approximately 50%, and concomitant treatment of losartan with rifampicin (inducer of metabolism enzymes) gave a 40% reduction in plasma concentration of the active metabolite. The clinical relevance of this effect is unknown. No difference in exposure was found with concomitantly treatment with fluvastatin (weak inhibitor of CYP2C9).
As with other drugs that block angiotensin II or its effects, concomitant use of other drugs which retain potassium (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. Co-medication is not advisable.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Co-administration of lithium and losartan should be undertaken with caution. If this combination proves essential, serum lithium level monitoring is recommended during concomitant use.
When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective cyclooxygenase 2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Concomitant use of angiotensin II receptor antagonists and ACE-inhibitors (dual blockade of renin-angiotensin-aldosterone system) should be limited (individually defined cases) with close monitoring of renal function. There are data that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) as compared to use of a single angiotensin II antagonist.
Peculiarity of administration.
Angioneurotic oedema. During the drug therapy, patients with a history of angioedema (swelling of the face, lips, throat, and/ or tongue) should be closely monitored.
Arterial hypotension and electrolyte/fluid imbalance.
Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of losartan, or a lower starting dose should be used. This also applies to children aged over 6 years.
Electrolyte imbalances are common in patients with renal impairment (with or without diabetes) and should be addressed. The plasma concentrations of potassium (possible hyperkalaemia) as well as creatinine clearance values should be closely monitored; especially patients with heart failure and a Creatinine Clearance between 30-50 ml/ min should be closely monitored.
The concomitant use of potassium sparing diuretics, potassium supplements and potassium containing salt substitutes with losartan is not recommended.
Hepatic function impairment.
Based on pharmacokinetic data, which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment.
The drug is not recommended for use in children with hepatic impairment.
Renal function impairment.
As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the rennin- angiotensin- aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction).
Medicinal products that affect the renin-angiotensin-aldosterone system may cause increases in blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. These changes in renal function may be reversible upon discontinuation of therapy. Klosart® 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 function impairment.
The drug is not recommended in children with glomerular filtration rate < 30ml/ min/ 1.73 m2 as no data are available.
Renal function should be regularly monitored during treatment with Klosartas it may deteriorate. This applies particularly when losartan is given in the presence of other conditions (fever, dehydration) likely to impair renal function.
Concomitant use of Klosart and ACE-inhibitors has shown to impair renal function, therefore, such combination is not recommended.
There is no experience in safety of losartan in patients with recent kidney transplantation.
Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Klosart® is not recommended in this population.
Coronary heart disease and cerebrovascular disease.
As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.
In patients with heart failure, with or without renal impairment, there is - as with other drugs acting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment.
There is no sufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV) as well as in patients with heart failure and symptomatic life threatening cardiac arrhythmias.Therefore, losartan should be used with caution in these patient groups. The combination of losartan with a β -blocker should be used with caution.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Other warnings and precautions.
As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.
Administration in pregnancy and lactation.
Pregnancy. Losartan is not recommended during the first trimester of pregnancy, and is contraindicated during the second and the third trimesters of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there are no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitor (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRA should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, arterial hypotension, hyperkalaemia).
Should exposure to AIIRA have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken losartan should be closely observed for hypotension.
Lactation. Because no information is available regarding the use of losartan during breastfeeding, the drug is not recommended. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a new-born or preterm infant.
Influence or alertness while driving and operating other machines.
The data on the effects of losartan on the ability to drive and use other machines are limited. It must be borne in mind that such adverse effects as dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.
Posology and administration.
The tablets are taken regardless of meal, followed by 1 glass of water.
The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily (in the morning).
Klosart® may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide).
Hypertensive type II diabetic patients with proteinuria ≥ 0.5 g/day.
The usual starting dose of Klosart® is 50 mg once daily. The dose may be increased to 100 mg once daily based on blood pressure response from one month onwards after initiation of therapy. Klosart® may be administered with other antihypertensive agents (diuretics, calcium channel blockers, α- or β-blockers, and centrally acting agents) as well as with insulin and other commonly used hypoglycaemic agents (e.g. sulfonylureas, glitazones and glycosidase inhibitors).
The usual starting dose of losartan for patients with chronic heart failure is 12.5 mg once daily. As a rule, the dose is titrated at weekly intervals (i.e. 12.5 mg per day, 25 mg per day, 50 mg per day) till the usual maintenance dose of 50 mg (1 tablet of Klosart 50 mg) once daily, depending on individual tolerance.
Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG.
The usual starting dose is 50 mg once daily. A low dose of hydrochlorothiazide should be added and/or the dose of losartan should be increased to 100 mg once daily based on blood pressure response.
Use in patients with intravascular volume depletion.
For patients with intravascular volume depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg once daily is recommended.
Use in patients with renal impairment and haemodialysis patients.
No initial dosage adjustment is necessary when prescribing Klosart in patients with renal impairment and in haemodialysis patients.
Use in patients with a history of hepatic impairment.
A lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience in patients with severe hepatic impairment; therefore Klosart® is contraindicated in this group of patients.
Use in children over 6 years old.
For children who can swallow tablets, and whose body mass is >20 to
In patients >50 kg, the usual dose is 50 mg once daily. In exceptional cases the dose can be adjusted to a maximum of 100 mg once daily. Doses above 1.4 mg/ kg (or in excess of 100 mg) daily have not been studied in paediatric patients.
Klosart® is not recommended for use in children with impaired hepatic function.
Klosart® is also not recommended for use in children with glomerular filtration rate < 30 ml/min/1.73 m2, as no data are available.
Use in patients aged over 75 years.
The therapy should be initiated with 25 mg daily. Dosage adjustment is not usually necessary.
Safety and efficacy of using Klosart in children less than 6 years old have not been determined.
Symptoms of overdose.
Limited data are available with regard to overdose. The most likely manifestation of overdose would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.
The treatment depends on the time of drug intake and kind and severity of symptoms. Stabilisation of the circulatory system should be given priority. After oral intake of losartan the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary. Neither losartan nor the active metabolites can be removed by haemodialysis.
Nervous system disorders: dizziness, somnolence, headache, insomnia, muscle cramps, paresthesia, stroke, migraine, dysgeusia.
Ear and labyrinth disorders: vertigo, tinnitus.
Psychiatric disorder: depression.
Cardiac disorders: palpitation, syncope, angina, tachycardia, atrial fibrillation.
Vascular disorders: symptomatic hypotension (especially in patients with intravascular dehydration, for example, patients with severe heart failure or under treatment with diuretics in high doses), dose-dependent orthostatic effect.
Gastrointestinal tract disorders: abdominal pain, dyspepsia, constipation, diarrhoea, pancreatitis, nausea, vomiting.
Hepatobiliary system disorders: hepatitis, abnormal liver function.
Respiratory system disorder: cough, dyspnoea, rhinitis, sinusitis, pharyngitis, upper respiratory tract infection.
Kidney and urinary tract disorders: changes in renal function including renal failure in patients at risk (such changes in renal function may be reversible with cessation of therapy), urinary tract infection).
Blood and lymphatic system disorders: anaemia, thrombocytopenia.
General disorders and administration site conditions: asthenia/fatigue, malaise, oedema, flu-like symptoms.
Skin and subcutaneous tissue disorders: urticaria, pruritus, rash, photosensitivity, erythroderma.
Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, rhabdomyolysis.
Reproductive system and breast disorders: erectile dysfunction/impotence.
Immune system disorders: hypersensitivity reactions (anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue) in some patients angioedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors; vasculitis, including Henoch-Schonlein purpura.
Laboratory tests: hypoglycaemia, hyperglycaemia, hyponatremia, increased ALT levels, increased blood urea levels, increased serum creatinine levels.
Store at the temperature not more than 25 °C in the original package.
Keep out of reach of children.
Tablets 25 mg, 50 mg.
14 tablets are in a blister; 1 or 2, or 6 blisters are in a carton box.
Tablets 100 mg.
14 tablets are in a blister; 1 or 2, or 6 blisters are in a carton box.
10 tablets are in a blister; 3 or 10 blisters are in a carton box.
Conditions of supply.
“KUSUM PHARM” LLC.
54, Skryabina Str., Sumy 40020, Ukraine.
Date of last revision.
1 film coated tablet contains Losartan potassium 25 mg or 50 mg; Simple medications of angiotensine II receptors antagonists.
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