Besartan

Losartan potassium (Besartan): White, oval, biconvex, film coated tablets with "BERLIN" on one side and scored between L and 50 on the other side.
Each Film-Coated Tablet contains: Losartan Potassium, USP 50 mg.
Excipients/Inactive Ingredients: Core Tablet: Mannitol, Lactose Monohydrate, Microcrystalline Cellulose, Pregelatinized Starch, Polysorbate 80, Magnesium Stearate.
Film coating solution: Hydroxypropyl Methyl Cellulose E5, Hydroxypropyl Methyl Cellulose E15, Polyethylene Glycol 6000, Titanium Dioxide, Talcum.

Pharmacotherapeutic group: Angiotensin II antagonists, plain. ATC code: C09CA01.
Pharmacology: Pharmacodynamics: Losartan is a synthetic oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT₁ receptor found in many tissues (e.g. 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 selectively blocks the AT₁ receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.
Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable bradykinin-mediated effects.
During administration of losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase 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, PRA and angiotensin II values fell within three days 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 on a weight for weight basis.
Hypertension Studies: In controlled clinical studies, once-daily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurement of blood pressure 24 hours post-dose relative to 5-6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70-80% of the effect seen 5-6 hours post-dose.
Discontinuation of losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, losartan had no clinically significant effect on heart rate.
Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.
LIFE-Study: The Losartan Intervention for Endpoint Reduction in Hypertension [LIFE] study was a randomized, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG-documented left-ventricular hypertrophy. Patients were randomized to once daily losartan 50 mg or once daily atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. Other antihypertensive, with the exception of ACE-inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach the goal blood pressure.
The mean length of follow up was 4.8 years.
The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95% confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.
Race: In the LIFE-Study, Black patients treated with losartan had a higher risk of suffering the primary combined endpoint, i.e. a cardiovascular event (e.g. cardiac infarction, cardiovascular death) and especially stroke, than the Black patients treated with atenolol. Therefore, the results observed with losartan in comparison with atenolol in the LIFE study with regard to cardiovascular morbidity/mortality do not apply for Black patients with hypertension and left ventricular hypertrophy.
RENAAL Study: The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan RENAAL study was a controlled clinical study conducted worldwide in 1513 Type 2 diabetic patients with proteinuria, with or without hypertension. 751 patients were treated with losartan.
The objective of the study was to demonstrate a nephroprotective effect of losartan potassium over and above the benefit of lowering blood pressure.
Patients with proteinuria and a serum creatinine of 1.3-3.0 mg/dL were randomized to receive losartan 50 mg once a day, titrated if necessary, to achieve blood pressure response, or to placebo, on a background of conventional antihypertensive therapy excluding ACE-inhibitors and angiotensin II antagonists. Investigators were instructed to titrate the study medication to 100 mg daily as appropriate; 72% of patients were taking the 100 mg daily dose for the majority of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha- and beta-receptor blockers and also centrally acting antihypertensive) were permitted as supplementary treatment depending on the requirement in both groups. Patients were followed up for up to 4.6 years (3.4 years on average). The primary endpoint of the study was a composite endpoint of doubling of the serum creatinine end-stage renal failure (need for dialysis or transplantation) or death.
The results showed that the treatment with losartan (327 events) as compared with placebo (359 events) resulted in a 16.1% risk reduction (p=0.022) in the number of patients reaching the primary composite endpoint. For the following individual and combined components of the primary endpoint, the results showed a significant risk reduction in the group treated with losartan: 25.3% risk reduction for doubling of the serum creatinine (p=0.006); 28.6% risk reduction for end-stage renal failure (p=0.002); 19.9% risk reduction for end-stage renal failure or death (p=0.009); 21.0% risk reduction for doubling of serum creatinine or end-stage renal failure (p=0.01).
All-cause mortality rate was not significantly different between the two treatment groups. In this study, losartan was generally well tolerated, as shown by a therapy discontinuation rate on account of adverse reactions that was comparable to the placebo group.
ELITE I and ELITE II Studies: In the ELITE Study carried out over 48 weeks in 722 patients with heart failure (NYHA Class II-IV), no difference was observed between the patients treated with losartan and those treated with captopril was observed with regard to the primary endpoint of a long-term change in renal function. The observation of the ELITE I Study, that compared with captopril, losartan reduced the mortality risk, was not confirmed in the subsequent ELITE II Study, which is described in the following.
In the ELITE II Study, losartan 50 mg once daily (starting dose 12.5 mg, increased to 25 mg, then 50 mg once daily) was compared with captopril 50 mg three times daily (starting dose 12.5 mg, increased to 25 mg and then to 50 mg three times daily). The primary endpoint of this prospective study was the all-cause mortality. In this study, 3152 patients with heart failure (NYHA Class II-IV) were followed for almost two years (median: 1.5 years) to determine whether losartan is superior to captopril in reducing all-cause mortality. The primary endpoint did not show any statistically significant difference between losartan and captopril in reducing all-cause mortality.
In both comparator-controlled (not placebo-controlled) clinical studies on patients with heart failure the tolerability of losartan was superior to that of captopril, measured based on a significantly lower rate of discontinuations of therapy on the account of adverse reactions and a significantly lower frequency of cough.
An increased mortality was observed in ELITE II in the small subgroup (22% of all HF patients) taking beta-blockers at baseline.
Pharmacokinetics: Absorption: Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.
Distribution: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres.
Biotransformation: About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of ¹⁴C-labelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed.
Elimination: Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, 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. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma. Both biliary and urinary excretions contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration of ¹⁴C-labelled losartan in man, about 35%/43% of radioactivity is recovered in the urine and 58%/50% in the faeces.
Characteristics in patients: In elderly hypertensive patients, the plasma concentrations of losartan and its active metabolite do not differ essentially from those found in young hypertensive patients.
In female hypertensive patients, the plasma levels of losartan were up to twice as high as in male hypertensive patients, while the plasma levels of the active metabolite did not differ between men and women.
In patients with mild to moderate alcohol-induced hepatic cirrhosis, the plasma levels of losartan and its active metabolite after oral administration were respectively 5 and 1.7 times higher than in young male volunteers.
Plasma concentrations of losartan are not altered in patients with a creatinine clearance above 10 mL/minute. Compared to patients with normal renal function, the AUC for losartan is about 2-times higher in haemodialysis patients.
The plasma concentrations of the active metabolite are not altered in patients with renal impairment or in haemodialysis patients.
Neither losartan nor the active metabolite can be removed by haemodialysis.
Pharmacokinetics in paediatric patients: The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients >1 month to <16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/kg of losartan (mean doses).
The results showed that the active metabolite is formed from losartan in all age groups. The results showed roughly similar pharmacokinetic parameters of losartan following oral administration in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing preschool children with adolescents these differences became statistically significant. Exposure in infants/toddlers was comparatively high.

Treatment of essential hypertension in adults and in children and adolescents 6-18 years of age.
Treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria ≥0.5 g/day as part of an antihypertensive treatment.
Reduction in the risk of stroke in adult hypertensive patients with left ventricular hypertrophy documented by ECG (see Pharmacology: Pharmacodynamics: LIFE study: Race under Actions).

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) (see Contraindications, Precautions, Interactions, and Pharmacology: Pharmacodynamics under Actions).
Hypertensive type II diabetic patients with proteinuria ≥0.5 g/day: The usual starting dose 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. Losartan may be administered with other antihypertensive agents (e.g. diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) (see Contraindications, Precautions, Interactions, and Pharmacology: Pharmacodynamics under Actions) as well as with insulin and other commonly used hypoglycemic agents (e.g. sulfonylureas, glitazones and glucosidase inhibitors).
Heart Failure: The usual initial dose of losartan in patients with heart failure is 12.5 mg once daily. The dose should generally be titrated at weekly intervals (i.e. 12.5 mg daily, 25 mg daily, 50 mg daily, 100 mg daily, up to a maximum dose of 150 mg once daily) as tolerated by the patient.
Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG: The usual starting dose is 50 mg of losartan 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.
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 should be considered (see Precautions).
Use in patients with renal impairment and haemodialysis patients: No initial dosage adjustment is necessary in patients with renal impairment and in haemodialysis patients.
Use in patients with 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 patients with severe hepatic impairment (see Contraindications and Precautions).
Paediatric population: 6 months-less than 6 years: The safety and efficacy of children aged 6 months to less than 6 years has not been established. Currently available data are described in Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions but no recommendation on posology can be made.
6 years to 18 years: For patients who can swallow tablets, the recommended dose is 25 mg once daily in patients >20 to <50 kg. (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 >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.
Losartan is not recommended for use in children under 6 years old, as limited data are available in these patient groups.
It is not recommended in children with glomerular filtration rate <30 mL/min/1.73 m², as no data are available.
Losartan is also not recommended in children with hepatic impairment (see also Precautions).
Use in Elderly: Although consideration should be given to initiating therapy with 25 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.
Losartan (Besartan) tablets should be swallowed whole with a glass of water.
Losartan (Besartan) tablets may be administered with or without food.

Symptoms of intoxication: Limited data are available with regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.
Treatment of intoxication: If symptomatic hypotension should occur, supportive treatment should be instituted.
Measures are depending on the time of medicinal product intake and kind and severity of symptoms. Stabilization of the cardiovascular system should be given priority. After oral intake, 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 metabolite can be removed by hemodialysis.

Hypersensitivity to losartan or any component of the formulation.
Severe hepatic impairment.
The concomitant use of losartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).
Pregnancy (2nd and 3rd trimester).

Hypersensitivity: Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored (see Adverse Reactions).
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, diarrhea or vomiting. These conditions should be corrected prior to administration of losartan, or a lower starting dose should be used (see Dosage & Administration). This also applies to children 6 to 18 years of age.
Electrolyte imbalances: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalemia was higher in the group treated with losartan as compared to the placebo group (see Adverse Reactions). Therefore, the plasma concentrations of potassium 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 (see Interactions).
Hepatic 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. Therefore, losartan must not be administered in patients with severe hepatic impairment (see Dosage & Administration, Contraindications, and Pharmacology: Pharmacokinetics under Actions).
Losartan is not recommended in children with hepatic impairment (see Dosage & Administration).
Renal 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 renin-angiotensin-aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction). As with other medicinal products that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported 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 paediatric patients with renal impairment: Losartan is not recommended in children with glomerular filtration rate <30 mL/min/1.73 m² as no data are available (see Dosage & Administration). Renal function should be regularly monitored during treatment with losartan as it may deteriorate. This applies particularly when losartan (Besartan) is given in the presence of other conditions (fever, dehydration) likely to impair renal function.
Concomitant use of losartan and ACE-inhibitors has shown to impair renal function. Therefore, concomitant use is not recommended (see Interactions).
Renal transplantation: There is no experience in patients with recent kidney transplantation.
Primary hyperaldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of losartan is not recommended.
Coronary heart disease and cerebrovascular disease: As with any antihypertensive agents, excessive blood pressure decrease in patients with ischemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.
Heart failure: In patients with heart failure, with or without renal impairment, there is - as with other medicinal products 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 beta-blocker should be used with caution (see Pharmacology: Pharmacodynamics under Actions).
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.

Pregnancy: The use of losartan is not recommended during the first trimester of pregnancy (see Precautions). The use of losartan is contraindicated during the 2^nd and 3^rd trimester of pregnancy (see Contraindications and Precautions).
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 is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of medicinal products. 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 losartan 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 human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
Should exposure to losartan 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 (see Contraindications and Precautions).
Lactation: Because no information is available regarding the use of losartan during breastfeeding, losartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Losartan has been evaluated in clinical studies as follows: In a controlled clinical trial in >3,000 adult patients 18 years of age and older for essential hypertension.
In a controlled clinical trial in 177 hypertensive pediatric patients 6 to 16 years of age.
In a controlled clinical trial in >9,000 hypertensive patients 55 to 80 years of age with left ventricular hypertrophy (see Pharmacology: Pharmacodynamics: LIFE-Study under Actions).
In controlled clinical trials in >7,700 adult patients with chronic heart failure (see Pharmacology: Pharmacodynamics: ELITE I and ELITE II under Actions).
In a controlled clinical trial in >1,500 type 2 diabetic patients 31 years of age and older with proteinuria (see Pharmacology: Pharmacodynamics: REENAL Study under Actions).
In the clinical studies performed for losartan potassium, dizziness was the most common reported adverse event.
The frequency of adverse reactions listed as follows is defined using the following convention: very common (≥1/10); common (≥1/100, to <1/10); uncommon (≥1/1,000, to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
The frequency of adverse reactions identified from placebo-controlled clinical studies and post marketing experience.
Blood and lymphatic system disorders: Anemia: Chronic Heart Failure (common); Post-marketing experience (frequency not known).
Thrombocytopenia: Post-marketing experience (frequency not known).
Immune System Disorders: Hypersensitivity reactions, anaphylactic reactions, angioedema*, and vasculitis**: Post-marketing experience (rare).
Nervous System Disorders: Dizziness: Hypertension (common); Hypertensive patients with left ventricular hypertrophy (common); Chronic heart failure (common); Hypertension and type 2 diabetes with renal disease (common).
Somnolence: Hypertension (uncommon).
Headache: Hypertension (uncommon); Chronic heart failure (uncommon).
Sleep Disorders: Hypertension (uncommon).
Migraine: Post-marketing experience (frequency not known).
Dysgeusia: Post-marketing experience (frequency not known).
Ear and Labyrinth Disorders: Vertigo: Hypertension (common); Hypertensive patients with left ventricular hypertrophy (common).
Cardiac Disorders: Palpitations: Hypertension (uncommon).
Angina Pectoris: Hypertension (uncommon).
Syncope: Chronic heart failure (rare).
Atrial Fibrillation: Chronic heart failure (rare).
Cerebrovascular Accident: Chronic heart failure (rare).
Vascular Disorders: (Orthostatic) hypotension (including dose-related orthostatic effects)^║: Hypertension (uncommon); Chronic heart failure (common); Hypertension and type 2 diabetes with renal disease (common).
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea: Chronic heart failure (uncommon).
Cough: Chronic heart failure (uncommon); Post-marketing experience (frequency not known).
Gastrointestinal Disorders: Abdominal Pain: Hypertension (uncommon).
Diarrhoea: Chronic heart failure (uncommon).
Nausea: Chronic heart failure (uncommon).
Vomiting: Chronic heart failure (uncommon).
Hepatobiliary Disorders: Hepatitis: Post-marketing experience (frequency not known).
Liver Function Abnormalities: Post-marketing experience (frequency not known).
Skin and Subcutaneous Tissue Disorders: Urticaria: Chronic heart failure (uncommon); Post-marketing experience (frequency not known).
Pruritus: Chronic heart failure (uncommon); Post-marketing experience (frequency not known).
Rash: Hypertension (uncommon); Post-marketing experience (frequency not known).
Photosensitivity: Post-marketing experience (frequency not known).
Musculoskeletal and Connective Tissue Disorders: Myalgia: Post-marketing experience (frequency not known).
Arthralgia: Post-marketing experience (frequency not known).
Renal and Urinary Disorders: Renal Impairment: Chronic heart failure (common).
Renal Failure: Chronic heart failure (common).
Reproductive System and Breast Disorders: Erectile Dysfunction/Impotence: Post-marketing experience (frequency not known).
General Disorders and Administration Site Conditions: Asthenia: Hypertension (uncommon); Hypertensive patients with left ventricular hypertrophy (common); Chronic heart failure (uncommon); Hypertension and type 2 diabetes with renal disease (common).
Fatigue: Hypertension (uncommon); Hypertensive patients with left ventricular hypertrophy (common); Chronic heart failure (uncommon); Hypertension and type 2 diabetes with renal disease (common).
Edema: Hypertension (uncommon).
Malaise: Post-marketing experience (frequency not known).
Investigations: Hyperkalemia: Hypertension (common); Chronic heart failure (uncommon^†); Hypertension and type 2 diabetes with renal disease (common^‡).
Increased Alanine aminotransferase (ALT)^§: Hypertension (rare).
Increased in blood urea, serum creatinine, and serum potassium: Chronic heart failure (common).
Hyponatremia: Post-marketing experience (frequency not known).
Hypoglycemia: Hypertension and type 2 diabetes with renal disease (common).
*Including swelling of the larynx, glottis, face, lips, pharynx, and/or tongue (causing airway obstruction); in some of these patients, angioedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors.
**Including Henoch-Schönlein purpura.
^║Especially in patients with intravascular depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics.
^†Common in patients who received 150 mg losartan instead of 50 mg.
^‡ In a clinical study conducted in type 2 diabetic patients with nephropathy, 9.9% of patients treated with Losartan tablets developed hyperkalemia >5.5 mmol/L and 3.4% of patients treated with placebo.
^§Usually resolved upon discontinuation.
The following additional adverse reactions occurred more frequently in patients who received losartan than placebo (frequencies not known): back pain, urinary tract infection, and flu-like symptoms.
Renal and urinary disorders: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function including renal failure have been reported in patients at risk; these changes in renal function may be reversible upon discontinuation of therapy (see Precautions).
Pediatric population: The adverse reaction profile for pediatric patients appears to be similar to that seen in adult patients. Data in the pediatric population are limited.

Other antihypertensive agents may increase the hypotensive action of losartan. Concomitant use with other substances which may induce hypotension as an adverse reaction (like tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension.
Losartan is predominantly metabolized by cytochrome P450 (CYP) 2C9 to the active carboxy-acid metabolite. In a clinical trial, it was found that fluconazole (inhibitor of CYP2C9) decreases the exposure to the active metabolite by approximately 50%. It was found that 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 concomitant treatment with fluvastatin (weak inhibitor of CYP2C9).
As with other medicinal products that block angiotensin II or its effects, concomitant use of other medicinal products which retain potassium (e.g. potassium-sparing diuretics: amiloride, triamterene, spironolactone) 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. Very rare cases have also been reported with angiotensin II receptor antagonists. Co-administration of lithium and losartan (Besartan) 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 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.
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 frequency of adverse events such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications, Precautions, and Pharmacology: Pharmacodynamics under Actions).

Store at temperatures not exceeding 30°C. Protect from light.

Angiotensin II Antagonists

C09CA01 - losartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.

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