Instructions for Lozap film-coated tablets 100 mg blister No. 90
Composition
active ingredient: losartan;
1 tablet contains losartan potassium 12.5 mg; or 50 mg; or 100 mg;
excipients: microcrystalline cellulose, mannitol (E 421), crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, talc, white dye Sepifilm 752 (contains hypromellose, microcrystalline cellulose, macrogol stearate, titanium dioxide (E 171)), macrogol 6000.
Dosage form
Film-coated tablets.
Main physicochemical properties:
Lozap® (dosage 12.5 mg): oval biconvex, film-coated tablets, white or almost white in color;
Lozap® (dosage 50 mg): oval biconvex, film-coated tablets, white or almost white in color, with a score line, approximately 11.0 x 5.5 mm in size;
Lozap® (dosage 100 mg): oval biconvex, film-coated tablets, white or almost white in color, with a score line, approximately 14.0 x 7.0 mm in size.
Pharmacotherapeutic group
Simple preparations of angiotensin II receptor antagonists. ATC code C09C A01.
Pharmacological properties
Pharmacodynamics
Losartan is a synthetic angiotensin II (type AT1) receptor antagonist for oral administration. Angiotensin II, a potent vasoconstrictor, is the active hormone of the renin-angiotensin system and is one of the most important factors in the pathophysiology of arterial hypertension. Angiotensin II binds to the AT1 receptor, which is found in many tissues (e.g., 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 binds selectively to the AT1 receptor. In vitro and in vivo, losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block all physiologically relevant effects of angiotensin II, regardless of the source or route of synthesis.
Losartan binds selectively 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.
The use of losartan reduces the total number of deaths from cardiovascular causes, stroke, and myocardial infarction in patients with arterial hypertension with left ventricular hypertrophy, and provides kidney protection in patients with type II diabetes mellitus with proteinuria.
Pharmacokinetics
Absorption: After oral administration, losartan is well absorbed and undergoes first-pass metabolism to form the active carboxylic acid metabolite and inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached after 1 hour and 3-4 hours, respectively.
Distribution: Losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters.
Biotransformation. Approximately 14% of losartan is converted to the active metabolite after intravenous or oral administration. Following intravenous and oral administration of 14C-labeled losartan potassium, the radioactivity in circulating plasma is generally characterized by losartan and its metabolite. Minimal conversion of losartan to its active metabolite has been observed in approximately 1% of cases. Inactive metabolites are also formed in addition to the active metabolite.
Elimination. The plasma clearance of losartan and its active metabolite is 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 losartan is administered orally, approximately 4% of the dose is excreted unchanged in the urine, and approximately 6% of the dose is excreted in the urine as the active metabolite. The pharmacokinetics of losartan and its active metabolite are linear over oral doses of losartan potassium up to 200 mg.
After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of approximately
Pharmacokinetics in specific patient groups
Elderly patients.
The plasma concentrations of losartan and its active metabolite in elderly patients with arterial hypertension do not differ significantly from those in young patients with arterial hypertension.
Sex.
Plasma concentrations of losartan were 2-fold higher in hypertensive women compared to men. Concentrations of the active metabolite did not differ between men and women.
Liver and kidney dysfunction.
When administered orally to patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were 1.7-5 times higher, respectively, than in young male volunteers.
Plasma concentrations of losartan in patients with creatinine clearance above 10 ml/min did not differ from those in subjects with normal renal function. When comparing the area under the concentration curve (AUC) in patients with normal renal function, the AUC of losartan in patients undergoing homotransplantation was approximately 2-fold higher. Plasma concentrations of the active metabolite are not altered in patients with impaired renal function or in patients undergoing hemodialysis. Losartan and its active metabolite cannot be removed by hemodialysis.
Pharmacokinetics in children.
The pharmacokinetics of losartan were studied in 50 hypertensive children aged 1 month to 16 years after oral administration once daily at doses ranging from 0.54 to
0.77 mg/kg (average doses). The results showed that the active metabolite of losartan is formed in patients of all age groups. The results indicate approximately similar pharmacokinetics of losartan after oral administration in neonates and children under 2 years of age, preschool children, school-age children and adolescents. The pharmacokinetics of the metabolite differed more depending on the age group. When comparing preschool children and adolescents, such differences were statistically significant. Exposure in neonates and children under 2 years of age was relatively high.
Indication
Treatment of essential hypertension in adults, as well as children and adolescents aged 6 years and older.
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 aged 60 years and over) when the use of angiotensin converting enzyme (ACE) inhibitors is considered impossible due to incompatibility, especially in the presence of cough, or is contraindicated. Patients with heart failure whose condition has been stabilized on an ACE inhibitor should not be switched to losartan. The patient should have a left ventricular ejection fraction ≤ 40%, be clinically stable, and be on 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; severe liver dysfunction. The drug is contraindicated in pregnant women or women planning to become pregnant. Concomitant use of the drug with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus and renal impairment (GFR < 60 ml/min/1.73 m2).
Interaction with other medicinal products and other types of interactions
Other antihypertensive drugs may enhance the hypotensive effect of losartan. Concomitant use with other drugs that can induce such an adverse reaction as arterial hypotension (tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of arterial hypotension.
Losartan is metabolized primarily by the cytochrome P450 (CYP) 2C9 system to the active carboxylic acid metabolite. Fluconazole (a CYP2C9 inhibitor) reduces the exposure of the active metabolite by approximately 50%. Concomitant treatment with losartan and rifampicin (an inducer of metabolic enzymes) has been shown to result 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 CYP2C9 inhibitor).
Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium with ACE inhibitors. Cases have also been reported very rarely with angiotensin II receptor antagonists. Concomitant treatment with lithium and losartan should be undertaken with caution. If the combination is considered necessary, it is recommended that serum lithium levels be monitored during combination therapy.
With the simultaneous use of angiotensin II antagonists and non-steroidal anti-inflammatory drugs (e.g. selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, non-selective NSAIDs), the antihypertensive effect may be weakened. The simultaneous use of angiotensin II antagonists or diuretics with NSAIDs may lead to an increased risk of worsening of renal function, including the possible development of acute renal failure, as well as an increase in serum potassium, especially in patients with pre-existing impaired renal function. Such a combination should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated, and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
There is evidence that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared with the use of a single agent affecting the RAAS. Dual blockade should be limited to individually defined cases and accompanied by careful monitoring of blood pressure, renal function and electrolyte balance. Aliskiren should not be used concomitantly with losartan in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min) (see section "Contraindications").
Application features
Hypersensitivity
Angioedema: Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be monitored frequently.
Arterial hypotension and water and electrolyte imbalance
Symptomatic hypotension, especially after the first dose or after increasing the dose, 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 by reducing the initial dose of the drug (see "Method of administration and dosage"). The same recommendations apply to children aged 6 years and older.
Electrolyte imbalance
Electrolyte imbalance is common in patients with renal impairment (with or without diabetes mellitus) and should be considered. In a clinical trial in patients with type 2 diabetes mellitus and nephropathy, the incidence of hyperkalemia was higher with losartan compared to placebo. Therefore, frequent monitoring of plasma potassium and creatinine clearance should be considered, 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.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal function depression (including the development of acute renal failure). In this regard, dual blockade of the RAAS by the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended.
In case of absolute necessity of dual blockade of RAAS, it should be carried out under specialist supervision and with careful monitoring of renal function, electrolyte balance and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
The combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).
Liver dysfunction
Given the pharmacokinetic data indicating a significant increase in plasma concentrations of losartan in patients with cirrhosis, a dose reduction should be considered in patients with a history of hepatic impairment. There is no experience in patients with severe hepatic impairment.
Losartan is not recommended for use in children with liver impairment.
Kidney 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 or stenosis of the artery to a solitary kidney. These changes in renal function may be reversible upon discontinuation of therapy. Losartan 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 glomerular filtration rate
< 30 ml/min/1.73m2, as there are no relevant data on use.
Renal function should be monitored regularly during treatment with losartan, as it may deteriorate. This is especially true when losartan is used in the presence of other pathological conditions (fever, dehydration) that may affect renal function.
The simultaneous use of losartan and ACE inhibitors worsens kidney function, so this combination is not recommended.
Kidney transplantation.
There is no experience regarding the safety of the drug in patients who have recently undergone a kidney transplant.
Primary hyperaldosteronism.
Patients with primary hyperaldosteronism generally do not respond to drugs that inhibit the renin-angiotensin system. Therefore, losartan is not recommended for this group of patients.
Coronary artery disease and cerebrovascular disease.
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), and 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, the drug 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.
Use during pregnancy or breastfeeding
Pregnancy.
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.
Losartan should not be used by pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicine, its use should be discontinued immediately and replaced with another medicine approved for use in pregnancy.
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.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effect of the drug on the ability to drive and use machines. However, it should be borne in mind that side effects such as dizziness and drowsiness may occur, especially at the beginning of treatment and when the dose of the drug is increased.
Method of administration and doses
The tablets can be taken regardless of meals, washed down with 1 glass of water.
Arterial hypertension
Usually the initial and maintenance dose for most patients is 50 mg of the drug once a day (1 tablet of 50 mg). The maximum antihypertensive effect is achieved at
3-6 weeks after starting treatment with the drug. Some patients may benefit from increasing the dose to 100 mg once daily (in the morning).
Patients with hypertension and type 2 diabetes mellitus (proteinuria ≥ 0.5 g/day)
The usual starting dose is 50 mg (1 tablet of 50 mg) once daily. The dose may be increased to 100 mg once daily depending on blood pressure response 1 month after initiation of treatment. Losartan may be used with other antihypertensive agents (e.g. diuretics, calcium channel blockers, α- or β-blockers).
β-receptor blockers, centrally acting drugs), as well as with insulin and other widely used hypoglycemic drugs (e.g. sulfonylureas, glitazones and glucosidase inhibitors).
Heart failure
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 50 mg) once daily depending on individual tolerability.
Reducing the risk of stroke in patients with arterial hypertension and ECG-confirmed left ventricular hypertrophy
The usual starting dose is 50 mg losartan (1 tablet of 50 mg) once daily. Depending on the response to blood pressure, low-dose hydrochlorothiazide should be added to the treatment and/or the dose of losartan should be increased to 100 mg once daily.
Certain groups of patients.
Use in patients with reduced circulating blood volume
Patients with reduced circulating blood volume (e.g., due to treatment with high doses of diuretics) should begin therapy with a dose of 25 mg once daily.
Use in patients with renal impairment and patients undergoing hemodialysis
When prescribing losartan to patients with impaired renal function, as well as patients undergoing hemodialysis, initial dose adjustment is not required.
Use in patients with hepatic impairment
For patients with a history of hepatic impairment, a lower dose should be considered. There is no experience in patients with severe hepatic impairment, therefore losartan is contraindicated in this group of patients.
Use in elderly patients
There is generally no need to adjust the starting dose for elderly patients, although consideration should be given to prescribing the drug at a starting dose of 25 mg for patients aged 75 years and older.
Children
Data on the efficacy and safety of losartan in children and adolescents aged 6 years and older for the treatment of hypertension are limited. There are also limited pharmacokinetic data in children with hypertension aged 1 month and older.
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 daily. In exceptional cases, the dose may be increased to a maximum of 50 mg once daily. The dose should be adjusted depending on the effect on blood pressure.
In patients weighing more than 50 kg, the usual single 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.
Losartan is not recommended for use in children under 6 years of age, as there is insufficient data on the use of the drug in this group of patients.
The drug is not recommended for use in children with glomerular filtration rate
< 30 ml/min/1.73m2, as there are no relevant data on use.
Losartan is also not recommended for use in children with impaired liver function.
Children
Safety and efficacy data in children aged 6 months to 6 years have not been established. Currently available data are presented in the Pharmacological Properties section, but no dosage recommendations can be made for children under 6 years of age.
Overdose
Symptoms of intoxication. No cases of overdose have been reported. The most likely symptoms, depending on the amount of overdose, will be arterial hypotension, tachycardia; bradycardia is possible.
Treatment of intoxication.
Treatment depends on the length of time that has passed since taking the drug, as well as the nature and severity of the symptoms.
The priority measure should be stabilization of cardiovascular function. After oral administration of the drug, 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
The most commonly reported adverse reaction was dizziness.
The frequency of adverse reactions listed below is defined as follows: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10000 to <1/1000; very rare: <1/10000; not known (cannot be estimated from the available data).
Arterial hypertension.
From the nervous system: often - dizziness, vertigo; infrequently - drowsiness, headache, insomnia, muscle cramps.
Vascular system: infrequently - symptomatic hypotension (especially in patients with intravascular dehydration, for example, patients with severe heart failure or when treated with high doses of diuretics), dose-dependent orthostatic effect, rash.
On the part of the digestive tract: infrequently - abdominal pain, dyspepsia, constipation.
Respiratory system: cough, runny nose, sinusitis, pharyngitis, upper respiratory tract infection.
General condition and disorders related to the method of administration of the drug: infrequently - asthenia, weakness, edema.
Laboratory values. Clinically significant changes in standard laboratory values have rarely been associated with the use of losartan tablets. ALT levels have been rarely increased and usually normalized after discontinuation of the drug. Hyperkalemia (serum potassium level > 5.5 mmol/L) has been observed in 1.5% of patients with arterial hypertension.
Patients with left ventricular hypertrophy.
From the nervous system: often - dizziness.
From the side of the organs of hearing and labyrinth: often - vertigo.
General conditions and disorders related to the method of administration of the drug: often - asthenia/weakness.
Chronic heart failure.
From the nervous system: infrequently - dizziness, headache; rarely - paresthesia.
Cardiac: rarely - syncope, atrial fibrillation, stroke.
Vascular system: infrequently - arterial hypotension, including orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: infrequently - dyspnea.
On the part of the digestive tract: infrequently - diarrhea, nausea, vomiting.
Skin and subcutaneous tissue disorders: infrequently - urticaria, itching, rash.
General disorders and administration-related disorders: infrequently - asthenia/weakness.
Laboratory parameters: infrequently - increased blood urea, serum creatinine and serum potassium.
Arterial hypertension and type II diabetes mellitus accompanied by kidney disease.
From the nervous system: often - dizziness.
From the vascular system: often - arterial hypotension.
General conditions and disorders related to the method of administration of the drug: often - asthenia/weakness.
Laboratory indicators: often - hypoglycemia, hyperkalemia.
The following adverse reactions occurred more frequently in patients taking losartan than in patients taking placebo.
Blood and lymphatic system disorders: anemia.
Cardiac: syncope, palpitations.
Vascular disorders: orthostatic hypotension.
Gastrointestinal: diarrhea.
Musculoskeletal and connective tissue disorders: back pain.
Renal and urinary disorders: urinary tract infections.
General conditions and disorders related to the method of administration of the drug: flu-like symptoms.
Laboratory parameters: In a clinical study in patients with type 2 diabetes mellitus and nephropathy, hyperkalemia > 5.5 mEq/L occurred in 9.9% of patients receiving losartan tablets and in 3.4% of patients receiving placebo.
Post-marketing surveillance.
The following adverse reactions have been reported during post-marketing surveillance.
From the blood and lymphatic system: anemia, thrombocytopenia.
From the side of the organs of hearing and labyrinth: ringing in the ears.
Immune system disorders: Rare: hypersensitivity reactions (anaphylactic reactions, angioedema, including laryngeal and glottis swelling leading to airway obstruction and/or swelling of the face, lips, pharynx and/or tongue); some patients had a history of angioedema associated with the use of other drugs, including ACE inhibitors; vasculitis, including Henoch-Schönlein purpura.
Nervous system: migraine, dysgeusia.
Respiratory, thoracic and mediastinal disorders: cough.
From the digestive tract: diarrhea, pancreatitis, vomiting.
General condition and disorders related to the method of administration of the drug: malaise.
From the hepatobiliary system: rarely - hepatitis, unknown - liver dysfunction.
Skin and subcutaneous tissue disorders: urticaria, itching, rash, photosensitivity, erythroderma.
Musculoskeletal and connective tissue disorders: myalgia, arthralgia, rhabdomyolysis.
Reproductive system and breast disorders: erectile dysfunction/impotence.
Renal and urinary disorders: As a consequence of inhibition of the renin-angiotensin-aldosterone system, changes in renal function, including renal failure, have been reported in patients at risk; such changes in renal function may be reversible upon discontinuation of therapy.
Mental disorders: depression.
Laboratory indicators: hyponatremia.
Children.
The adverse reaction profile in children is similar to that in adults. Data on adverse reactions in children are limited.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.
Packaging
No. 30 (10x3), No. 30 (15x2), No. 60 (10x6), No. 60 (15x4), No. 90 (10x9), No. 90 (15x6):
10 tablets in a blister; 3, 6 or 9 blisters in a cardboard box;
15 tablets in a blister; 2, 4 or 6 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
JSC "Saneka Pharmaceuticals".
Location of the manufacturer and its business address
Nitra 100, 920 27 Hlohovec, Slovak Republic.
