Instructions for Losartan-Teva film-coated tablets 100 mg No. 90
Composition
active ingredient: losartan potassium;
1 tablet contains 12.5 mg or 25 mg, or 50 mg, or 100 mg of losartan potassium;
Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch (corn), magnesium stearate, partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc.
Dosage form
Film-coated tablets.
Main physicochemical properties:
12.5 mg tablets: white, round, slightly convex, film-coated tablets, embossed with “L” on one side and plain on the other side;
25 mg tablets: white, oval, slightly convex, film-coated tablets, debossed with “2”, a score line and debossed with “5” on one side and a score line on the other side;
50 mg tablets: white, oval, slightly convex, film-coated tablets, embossed with “50” on one side and a breakline on the other;
100 mg tablets: white, oval, slightly convex, film-coated tablets, debossed with “100” on one side and a breakline on the other.
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 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 smooth muscle cell proliferation.
Losartan binds selectively to the AT1 receptor. In vitro and in vivo, losartan and its pharmacologically active metabolite, the carboxylic acid (E-3174), block all physiologically relevant effects of angiotensin II, regardless of the source or route of synthesis.
Losartan does not bind to or block other hormone receptors or ion channels important for cardiovascular regulation. Losartan does not inhibit angiotensin-converting enzyme (ACE) (kinase II), the enzyme that catalyzes the breakdown of bradykinin. Therefore, there is no potentiation of bradykinin-mediated adverse effects.
During the administration of losartan, the elimination of the negative feedback loop of angiotensin II on renin secretion increases plasma renin activity (PRA). This increase in PRA leads to an increase in plasma angiotensin II concentration. Despite this increase, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan treatment, plasma renin activity and angiotensin II levels return to baseline within 3 days.
Both losartan and its major metabolite have a higher affinity for AT1 receptors than for AT2 receptors. The active metabolite is 10–40 times more active than losartan.
Studies have shown that the concomitant use of ACE inhibitors with angiotensin II receptor antagonists in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with signs of target organ damage did not show a significant positive effect on renal function and/or cardiovascular system and mortality, while there was an increased risk of hyperkalemia, acute kidney injury and/or arterial hypotension compared with monotherapy. In connection with the above, ACE inhibitors and angiotensin II receptor blockers should not be used simultaneously in patients with diabetic nephropathy.
A study investigating the concomitant use of aliskiren with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease found a high risk of adverse events and the study was stopped. Fatal cardiovascular events and strokes were significantly more common in the aliskiren group than in the placebo group, and adverse events and serious adverse events such as hyperkalemia, hypotension, and renal dysfunction were also more common in the aliskiren group than in the placebo group.
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
More than 99% of losartan and its active metabolite are bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters.
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 associated with 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.
Breeding
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 terminal half-lives of approximately 2 hours and 6–9 hours, respectively. At a dose of 100 mg once daily, losartan and its active metabolite do not accumulate significantly in plasma.
Losartan and its metabolites are excreted in both bile and urine. After oral/intravenous administration of 14C-labeled losartan, approximately 35%/43% of the radiolabeled drug was recovered in urine and 58%/50% in feces.
Certain patient groups
Elderly patients
Plasma concentrations of losartan and its active metabolite in elderly hypertensive patients do not differ significantly from those in young hypertensive patients.
Sex
Plasma concentrations of losartan were 2-fold higher in hypertensive women compared to men, while plasma concentrations of the active metabolite were not significantly different between men and women.
Liver and kidney dysfunction
After oral administration, plasma concentrations of losartan and its active metabolite were 5 and 1.7 times higher, respectively, in patients with mild to moderate alcoholic cirrhosis 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. The area under the concentration-time curve (AUC) of losartan in patients with normal renal function was approximately 2-fold higher than in patients on hemodialysis.
Plasma concentrations of the active metabolite are not altered in patients with renal impairment and 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 mg/kg 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 pharmacokinetics of losartan after oral administration in neonates and preschool and school-aged children were similar.
The pharmacokinetic parameters of the metabolite varied more depending on the age group. In 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 arterial hypertension in adults and children aged 6 years and older.
- Treatment of kidney disease in adult patients with arterial hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day - as part of combination antihypertensive therapy.
- Treatment of chronic heart failure in adults when the use of angiotensin-converting enzyme (ACE) inhibitors is considered impossible due to incompatibility, especially in the case of cough, or is contraindicated. Patients with heart failure whose condition has been stabilized on an ACE inhibitor should not be transferred to losartan. In the treatment of chronic heart failure, the patient's left ventricular ejection fraction should be ≤ 40% and the condition should be clinically stable.
- Reduction in the risk of stroke in adult patients with arterial hypertension and left ventricular hypertrophy, as documented by ECG.
Contraindication
Hypersensitivity to the active substance or to any of the excipients.
Pregnancy or planning to become pregnant (see section "Use during pregnancy or breastfeeding").
Severe liver failure.
Concomitant use of losartan with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal insufficiency (glomerular filtration rate (GFR) <2).
Breastfeeding period.
Children's age up to 6 years.
Interaction with other medicinal products and other types of interactions
Other antihypertensive drugs may enhance the hypotensive effect of losartan. Drugs that may cause hypotension include tricyclic antidepressants, antipsychotics, baclofen, amifostine. Concomitant use of these drugs with antihypertensive drugs increases the risk of hypotension. Losartan is metabolized primarily by the cytochrome P450 (CYP) 2C9 system to form the active carboxylic acid metabolite. Fluconazole (a CYP2C9 inhibitor) has been reported to reduce the exposure of the active metabolite by approximately 50%. Concomitant use of 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).
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 toxic effects have been reported with concomitant use of lithium with ACE inhibitors. Very rare cases have also been reported 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 concomitant treatment.
Concomitant use of angiotensin II receptor antagonists and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. selective cyclooxygenase-2 (COX-2) inhibitors, acetylsalicylic acid at anti-inflammatory doses, non-selective NSAIDs) may result in attenuation of the antihypertensive effect. Concomitant use of angiotensin II antagonists or diuretics with NSAIDs increases the risk of worsening of renal function, including acute renal failure, and increases in serum potassium, especially in patients with pre-existing renal impairment. This combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and renal function may be monitored after initiation of concomitant therapy and periodically thereafter.
In the case of dual blockade with drugs (for example, adding an ACE inhibitor to the use of angiotensin II receptor antagonists), careful monitoring of renal function is necessary and, if necessary, limiting concomitant medication.
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) compared with the use of a single RAAS agent.
Application features
Increased sensitivity
Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be particularly monitored.
Arterial hypotension and water and electrolyte imbalance
Symptomatic hypotension, especially after the first dose or after dose increases, may occur in patients with reduced intravascular volume or sodium depletion caused by potent diuretics, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected before initiating treatment with losartan or the initial dose should be reduced. These recommendations also apply to children aged 6 years and older.
Electrolyte imbalance
Electrolyte imbalance is common in patients with renal impairment (with or without diabetes) and should be considered. In patients with type 2 diabetes and nephropathy, hyperkalemia has been reported to occur more frequently with losartan than with 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 potassium-containing salt substitutes is not recommended.
Liver dysfunction
Since pharmacokinetic data indicate 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 therapeutic experience with losartan in patients with severe hepatic impairment, and losartan should not be used in such patients.
Losartan is not recommended for use in children with liver impairment.
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 heart failure or pre-existing renal impairment).
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
Losartan is not recommended for use in children with a glomerular filtration rate of 2, as there are no adequate data on such use.
Renal function should be monitored regularly during treatment with losartan, as it may deteriorate, especially if losartan is used in the presence of other pathological conditions (fever, dehydration) that may affect renal function.
Concomitant use of losartan and ACE inhibitors worsens renal function, so this combination is not recommended.
Kidney transplantation
There are no data on 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 antihypertensive drugs that act by inhibiting 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 renal impairment (often acute) in patients with heart failure with or 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 such patients. Caution should be exercised when combining losartan with β-blockers.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, the drug should be administered with extreme caution to patients with aortic or mitral valve stenosis and obstructive hypertrophic cardiomyopathy.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended.
In cases where dual blockade is considered absolutely necessary, it should be carried out only under specialist supervision, with close monitoring of renal function, fluid and electrolyte balance and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be administered concomitantly in patients with diabetic nephropathy.
Pregnancy
Losartan should not be used in pregnant women or in women planning to become pregnant. Unless therapy with losartan is considered essential, patients 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 losartan should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Other caveats
Losartan and other angiotensin antagonists are less effective in lowering blood pressure in black patients than in non-black patients, possibly because of lower renin activity in black patients with hypertension.
Losartan-Teva contains lactose. Patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy
Patients planning pregnancy should be changed to alternative antihypertensive treatments with an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately and, if appropriate, alternative therapy should be started.
It has been established that the use of ARAII during the II and III trimesters of pregnancy induces fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) in humans.
If there have been cases of use of losartan from the second trimester of pregnancy, it is recommended to perform an ultrasound examination of renal function and the condition of the skull bones.
Infants whose mothers took losartan during pregnancy should be closely observed for signs of hypotension.
Breast-feeding
Losartan should not be used during breastfeeding. Alternative treatments with better established safety profiles during breastfeeding should be used during lactation.
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
Losartan tablets should be taken with 1 glass of water. Take the drug regardless of meals.
Arterial hypertension
The usual starting and maintenance dose for most patients is 50 mg once daily. The maximum antihypertensive effect is achieved within 3–6 weeks of treatment. Some patients may benefit from increasing the dose to 100 mg once daily (in the morning).
Losartan can be used in combination with other antihypertensive drugs, especially diuretics (e.g. hydrochlorothiazide).
Patients with hypertension and type 2 diabetes with proteinuria ≥ 0.5 g/day
An initial dose of 50 mg once daily is recommended. 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-receptor blockers and centrally acting agents), as well as with insulin and other hypoglycaemic agents (e.g. sulphonylureas, glitazones and glucosidase inhibitors).
Heart failure
For patients with chronic heart failure, a starting dose of 12.5 mg losartan once daily is recommended. The dose is usually titrated at weekly intervals (i.e. 12.5 mg daily, 25 mg daily, 50 mg daily, 100 mg once daily to a maximum dose of 150 mg once daily), depending on individual tolerability.
Reduction in the risk of stroke in patients with arterial hypertension and left ventricular hypertrophy, documented by ECG
The recommended starting dose is 50 mg losartan 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.
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 start therapy with a dose of 25 mg of losartan once daily.
Use in patients with renal impairment and patients undergoing hemodialysis sessions
When prescribing losartan to patients with impaired renal function and 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 treating patients with severe hepatic impairment, therefore losartan is contraindicated in such patients.
Use in children
Data on the efficacy and safety of losartan in children aged 6 years and older for the treatment of hypertension are limited.
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.
For patients weighing more than 50 kg, the recommended 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 patient group.
The drug is not recommended for use in children with a glomerular filtration rate of 2, as there are no relevant data on use.
Use in elderly patients
As a rule, there is no need to adjust the initial dose for elderly patients, although it is possible to prescribe losartan at an initial dose of 25 mg in patients over 75 years of age.
Children.
Losartan is not recommended for use in children under 6 years of age, as data are limited in this patient group.
Overdose
Symptoms
Data on overdose with losartan are limited. Depending on the degree of intoxication, symptoms such as hypotension, tachycardia, bradycardia, which may occur due to parasympathetic (vagal) stimulation, may occur.
Treatment
Treatment depends on the time elapsed since taking the drug, the nature and severity of the symptoms. In the event of symptomatic hypotension, supportive therapy should be carried out. The priority measure should be stabilization of the cardiovascular system. After oral overdose, the use of activated charcoal in an appropriate dose is indicated. Recommended measures are stimulation of vomiting and gastric lavage. Later, the main vital signs of the body should be monitored and adjusted if necessary. Losartan and its active metabolites are not removed by hemodialysis.
Adverse reactions
The most common adverse event with losartan was dizziness.
From the side of the circulatory and lymphatic system: anemia, thrombocytopenia.
Immune system disorders: hypersensitivity reactions, anaphylactic reactions, angioedema* and vasculitis**.
Psychiatric: depression.
From the nervous system: dizziness, drowsiness, headache, sleep disorders, paresthesia, migraine, dysgeusia.
From the organs of hearing and balance: vertigo, tinnitus.
Cardiovascular system: palpitations, angina pectoris, syncope, atrial fibrillation, acute cerebrovascular accident, orthostatic hypotension*** (including dose-dependent orthostatic effects) II.
Respiratory, thoracic and mediastinal disorders: shortness of breath, cough.
On the part of the digestive system: abdominal pain, intestinal obstruction, diarrhea, nausea, vomiting.
Hepatobiliary disorders: pancreatitis, hepatitis, liver dysfunction.
Skin and subcutaneous tissue disorders: urticaria, pruritus, rash, photosensitivity.
Musculoskeletal and connective tissue disorders: myalgia, arthralgia, rhabdomyolysis.
Renal and urinary disorders: renal dysfunction, renal failure.
Reproductive system: erectile dysfunction/impotence.
General disorders: asthenia, fatigue, edema, malaise.
Investigations: hyperkalemia, increased alanine aminotransferase (ALT)§, increased blood urea, serum creatinine, and serum potassium, hyponatremia, hypoglycemia.
*Including swelling of the larynx, glottis, face, lips, pharynx and/or tongue (causing airway obstruction); some of these patients have been reported to have a history of angioedema associated with the use of other medicinal products, including ACE inhibitors.
**Including Henoch-Schönlein disease.
***Hypotension is not a common side effect in patients with hypertension, but is common in patients with heart failure and in patients with type 2 diabetes who have kidney disease and hypertension.
IIEspecially in patients with reduced circulating blood volume, including patients with severe heart failure or those receiving high doses of diuretics.
§Usually disappears after discontinuation of treatment.
The following additional adverse reactions occurred more frequently in patients taking losartan than in patients taking placebo: back pain, urinary tract infections, and flu-like symptoms.
Renal and urinary disorders: As a result of inhibition of the renin-angiotensin-aldosterone system, changes in renal function have been observed in patients at high risk. These changes may be reversible and disappear after discontinuation of therapy.
Use in pediatrics
The adverse reaction profile observed in children and adolescents is similar to that observed in adults. Data on the use of the drug in pediatrics are limited.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
10 tablets in a blister; 3 blisters in a cardboard box (12.5 mg or 25 mg tablets, or 50 mg or 100 mg tablets) or 9 blisters in a cardboard box (50 mg tablets).
Vacation category
According to the recipe.
Manufacturers
Teva Pharmaceutical Plant JSC.
Teva Pharma S.L.U.
Location of manufacturers and addresses of their places of business.
Precinct 1; H-4042 Debrecen, Pallagi Str. 13, Hungary.
Poligono Industrial Malpica c/C No. 4, 50016, Zaragoza, Spain.
