INSTRUCTION for medical use KLOSART

APPROVED The Order of Ministry of Health of Ukraine 13.07.2018 1309 Registration certificate UA/8765/01/01 UA/8765/01/02 UA/8765/01/03 INSTRUCTION for medical use KLOSART Composition: active substance: losartan; 1 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. Basic physicochemical properties: yellow film coated round biconvex tablets. Pharmacotherapeutic group. Angiotensin II antagonists, plain. Code ATC C09C A01. Pharmacological properties. Pharmacodynamics. Losartan potassium is an angiotensin II (type АТ 1 ) 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 AT 1 receptor found in many tissues (vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological effects, 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 AT 1 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 AT 1 receptor blockade such as increasing the 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 increase of 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 initial values. Both losartan and its principal active metabolite have a greater affinity for the AT 1 -receptor than for the AT 2 -receptor. The active metabolite is 10- to 40- times more active than losartan. 1

Pharmacokinetics. After oral administration, losartan is well absorbed and undergoes metabolic transformations of the first passage. 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 of the drug is a part of the elimination of losartan and its active metabolite is approximately 35% of the dose falls into urine and almost 58% in the faeces. Elderly patients. No significant changes in the pharmacokinetic characteristics of elderly patients with hypertension were detected compared with younger patients. Gender. Concentrations of losartan in blood plasma in women with arterial hypertension were 2 times higher than those in men. The dependence of the concentration of active metabolite on the sex has not been detected. Liver and kidney dysfunction. Concentrations of losartan and its active metabolite in blood plasma in patients with impaired liver function are 1.7 to 5 times exceed these indices in patients with unchanged liver function. Concentrations of losartan in plasma of patients with creatinine clearance above 10 ml/min did not differ from those in healthy volunteers. The area under the concentration curve (AUC) in patients with severe renal impairment for losartan is about 2 times higher than in patients withnormal kidney function. Plasma concentrations of the active metabolite of losartan remained unchanged. Losartan and its active metabolite can not be removed by hemodialysis. Pharmacokinetics in childen. The active metabolite is formed from losartan in all age groups. The pharmacokinetic parameters of losartan following oral administration are roughly similar in new born 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 new born and children aged over 2 years is comparatively high. Clinical characteristics. Indications. Treatment of essential hypertension in adults and in children over 6 years old. Treatment of kidney disease in adult patients with arterial 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 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 losartan is not rational. 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. Contraindications. Hypersensitivity to losartan or to any excipient contained in the preparation. Severely impaired liver function. Pregnant women and women planning to conceive (see section Use during pregnancy or breastfeeding ). Concomitant use of losartan and aliskiren in patients with diabetes mellitus or with renal impairment (GFR < 60 ml/min/1.73m 2 ) is contraindicated (see sections Interaction with other 2

medicinal products and other types of interaction, Administration details, Administration and dosage ). Interaction with other medicinal products and other types of interaction. Other antihypertensive agents may increase the hypotensive action of losartan. Other drugs that may cause arterial hypotension include tricyclic antidepressants, antipsychotics, baclofen, and amifostine. The main or side effect of the simultaneous use of these drugs with antihypertensive drugs may be an increased risk of arterial hypotension. Losartan is predominantly metabolized 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 which block angiotensin II or its effects, the 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 increased potassium in serum. Concomitant use is not advisable. Reversible increase in serum lithium concentration and toxic manifestations were reported with the simultaneous use of lithium with ACE inhibitors. Very rare cases of angiotensin II receptor blockers have been reported. Simultaneous treatment with lithium and losartan should be done with caution. If the use of such a combination is considered necessary, it is recommended to check blood lithium levels during combined treatment. During concomitant use of angiotensin II antagonists and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., selective inhibitors of cyclooxygenase-2 (COX-2), acetylsalicylic acid at a dose having an anti-inflammatory effect, non-selective NSAIDs) may weaken the antihypertensive effect. Concomitant use of angiotensin II antagonists or NSAID diuretics may increase the risk of worsening of the kidney function, including the possible development of acute renal failure, as well as increased serum potassium levels, especially in patients with existing renal impairment. Such a combination should be prescribed with caution, especially for the elderly patients. Patients should undergo with an appropriate dehydration, monitoring of kidney function should also be considered after commencing coadministration and periodically during treatment. Double blockade (e.g. by adding an ACE inhibitor or aliskiren to angiotensin II receptor antagonists) should be limited to individually defined cases with careful control of blood pressure, renal function and electrolytes. Some studies have shown that in patients with established atherosclerosis, heart failure or diabetes with organ lesions, double blockade of renin-angiotensin system is associated with a higher incidence of hypotension, syncope, hyperkalemia and changes in renal function (including acute renal failure), compared to using a single drug having effect on the renin-angiotensin-aldosterone system. Concomitant administration of aliskiren and losartan is not recommended in patients with diabetes mellitus or in patients with renal failure (GFR < 60 ml/min) (see section Contraindications ). Administration details. Pregnancy. The use of angiotensin II receptor antagonists is contraindicated during pregnancy. Patients planning to conceive and receiving angiotensin II receptor antagonists should replace them by antihypertensive agents that have established safety profile for use in pregnancy. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be stopped immediately and alternative treatment should be started if necessary (see sections Contraindications and Use during pregnancy or breast-feeding ). Hypersensitivity. Angioneurotic edema. 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, 3

diarrhea 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 imbalance. Electrolyte imbalances are common in patients with renal impairment (with or without diabetes) and must be considered. The plasma concentrations of potassium (possible hyperkalemia) as well as creatinine clearance values, especially patients with heart failure and a Creatinine Clearance between 30-50 ml/ min should be closely monitored. The concomitant use of losartan and potassium sparing diuretics, potassium supplements and potassium containing salt substitutes 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. Changes in the function of the kidneys, including renal failure, associated with inhibition of the reninangiotensin system (especially renin-angiotensin-aldosterone-renal patients, i.e. patients with severe heart function impairment or with already existing renal dysfunction have been reported. ) Drugs affecting on renin-angiotensin-aldosterone system may increase blood urea and serum creatinine levels in patients with bilateral stenosis of the renal arteries, with renal artery stenosis, or with a stenosis of the artery of a single kidney. These changes in the function of the kidneys can be reversible after the termination of therapy. Caution should be exercised when administering losartan to patients with bilateral stenosis of the renal arteries or with a stenosis of the artery of a single kidney. Use in children with renal function impairment. The drug is not recommended in children with glomerular filtration rate < 30ml/ min/ 1.73 m 2 as there are no data available. During the period of application of losartan, the kidney function should be monitored regularly, since there is possible deterioration. Especially it is relted to such situations where losartan is used in the presence of other pathological conditions (e.g. fever, dehydration) that may affect the function of the kidneys. Concurrent administration of losartan and ACE inhibitors exacerbates renal function, therefore, such a combination is not recommended. Renal transplantation. There is no experience in safety of losartan in patients with recent kidney transplantation. Primary hyperaldosteronism. 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 group of patients. 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. Heart failure. As with other renin-angiotensin-aldosterone system agents, in patients with heart failure with / without kidney function, there is a risk of severe arterial hypotension and renal dysfunction, often acute. 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. 4

Other warnings and precautions. As established for ACE inhibitors, losartan and other angiotensin antagonists are less effective in lowering blood pressure in patients with Negroid race than in other patients, possibly due to low renin activity in a group of such patients with arterial hypertension. Double blockade of renin-angiotensin-aldosterone system (RAAS) When concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalaemia and renal dysfunction, including acute renal insufficiency. Therefore, double blockade of renin-angiotensin-aldosterone system by combining angiotensin II receptor blockers with ACE inhibitors or aliskirenom is not recommended (see section "Interaction with other drugs and other types of interactions"). In the event of the need for a double blockade, renin-angiotensinaldosterone system requires the supervision of a doctor, and also carefully check the function of the kidneys, blood levels of blood electrolytes and blood pressure. Angiotensin II receptor blockers and ACE inhibitors should not be administered simultaneously to patients with diabetic nephropathy. The combination with aliskiren is contraindicated in patients with diabetes mellitus or renal failure (GFR <60 ml/min/1.73 m 2 ). Use during pregnancy or breast-feeding. Pregnancy. The drug is contraindicated for use in pregnant women or in women planning to conceive (see sections Contraindications and Administration details ). If pregnancy is detected during treatment with this drug, it should be withdrawn immediately and replaced with other medicinal product permitted for use in pregnant women. Exposure to AIIRA therapy during the second and the third trimesters is known to induce foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If ARAII was used during the second trimester of pregnancy, it is recommended to conduct an ultrasound examination to check the function of the kidneys and the condition of the bones of the skull. The condition of newborns whose mothers have been used by ARAII should be frequently tested for the development of arterial hypotension. Breastfeeding. Because no information is available regarding the use of losartan during breastfeeding, the drug is not recommended. It is recommended to use alternative drugs with better established safety profiles during breastfeeding, especially when feeding newborns or preterm infants. Influence or alertness while driving and operating other machines. Data on the effects of losartan on the ability to drive or operate other mechanism are limited. However, the possibility of developing side effects such as dizziness and drowsiness, especially at the beginning of treatment and when increasing the dose of the drug, should be kept in mind. Dosage and administration. The tablets are taken regardless of meal, followed by 1 glass of water. Arterial hypertension. 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). Losartan may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide). Patients with arterial hypertension, Type II diabetes and proteinuria ( 0.5 g/day). Usually the initial dose of losartan is 50 mg once a day. The dose can be increased to 100 mg once a day, depending on what is the blood pressure reading 1 month after starting treatment. Losartan can be used with other antihypertensive drugs (diuretics, calcium channel blockers, α- or β-receptor blockers, centrally acting drugs), as well as insulin and other hypoglycemic agents (e.g., sulfonylureas, glitazones, and glucosidase inhibitors). 5

Heart failure. 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, 100 mg per day) to a maximum dose of 150 mg once daily depending on individual tolerability. 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. Depending on changes in blood pressure, it may be necessary to prescribe a low dose hydrochlorothiazide and / or increase the dose of losartan to 100 mg once daily. Special populations. 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 hemodialysis patients. No initial dosage adjustment is necessary when prescribing losartan in patients with renal impairment and in hemodialysis 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 losartan 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 more than 20 and less than 50 kg, the recommended dose is 25 mg once daily. In exceptional cases the dose can be increased to a maximum of 50 mg once daily. Dosage should be adjusted according to blood pressure response. In patients whose body mass is over 50 kg, the recommended dose is 50 mg once daily. In exceptional cases the dose can be adjusted to a maximum of 100 mg once daily.application of doses above 1.4 mg/ kg (or in over of 100 mg) daily have not been studied in children. Losartan is not recommended for use in children with impaired hepatic function. Losartan is also not recommended for use in children with glomerular filtration rate < 30 ml/min/1.73 m 2, as there is no data available. Use in patients aged over 75 years. The therapy should be initiated with 25 mg once daily. Usually dosage adjustment is not necessary. Children. Safety and efficacy of using losartan in children less than 6 years old have not been determined. Overdose. Symptoms of overdose. Limited data are available with regard to losartan overdose. The most likely manifestation of overdose is hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Treatment. Treatment depends on the time elapsed after taking the drug, as well as the nature and severity of the symptoms. The priority should be to stabilize the function of the cardiovascular system. After oral overdose, it is indicated the use of activated carbon in the appropriate dose. Later, you should often monitor the basic performance of the body and adjust if necessary. Losartan and its active metabolites are not removed during hemodialysis. Adverse reactions. 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), dosedependent orthostatic effect. 6

Gastrointestinal tract disorders: abdominal pain, dyspepsia, constipation, diarrhea, 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/weakness, increased fatigue, swelling, funguslike 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 Schoenlein-Henoch purpura. Laboratory tests: hypoglycaemia, hyperglycaemia, hyponatremia, increased ALT levels, increased blood urea levels, increased serum creatinine levels. Shelf-life. 3 years. Storage conditions. Store at the temperature below 25 C in the original package. Keep out of reach of children. Package. 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. By prescription. Manufacturer: KUSUM PHARM LLC. Address: 40020, Ukraine, Sumy oblast, Sumy, Skryabina Str., 54. Date of last revision. 13.07.2018 1309 7