AGILOSART®100

Composition: Each tablet contains:
Losartan potassium . . . . . . . . . . . . . . . . 100 mg
Presentation:
Cardboard box with 3 or 10 blisters of 10 film coated tablets.
Indications:
Treatment of essential hypertension in adults and in children over 6 years old: It may be used alone or in combination with other antihypertensive agents, including diuretics. Losartan should be administered to patients who are intolerant to angiotensin-converting enzyme inhibitors (ACEs).
Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day.
Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy.

Additional information

Dosage and administration

Dosage:
Treatment of hypertension:
Adults:
Dosage must be individualized and adjusted according to the patient's blood pressure response.
The usual starting and maintenance dose of Agilosart is 50 mg once daily for adult 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).
Generally, if administered dose can not control blood pressure adequately, the dose of antihypertensive drug should be adjusted periodically at 1-2 month intervals.
If blood pressure is not controlled with losartan alone, a low dose of diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect. Losartan may be administered with other antihypertensive agents. Losartan should not be combined with potassium-sparing diuretics, due to the increased risk of hyperkalemia.
Children:
There are limited data on the efficacy and safety of losartan in children and adolescents aged 6-16 years old for the treatment of hypertension. Limited pharmacokinetic data are available in hypertensive children above one month of age. Agilosart 100 is not suitable for children 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. Dose above 1.4mg/kg (or more than 100mg) daily have not been studied in paediatric patients.
Losartan is not recommended for use in children under 6 years of age, as limited data are available in this patient group.
Losartan is not recommended in children with liver failure or glomerular filtration rate < 30ml/min/1.73 m2, as no data are available.
Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day
The usual starting dose is 50mg once daily. The dose may be increased to 100mg 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) as well as with insulin and other commonly used hypoglycaemic agents (e.g. sulfonylureas, glitazones and glucosidase inhibitors).
Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy:
The usual starting dose is 50 mg of losartan once daily. A low dose of hydrochlorothiazide may be added, and/or the dose of losartan should be increased to 100 mg once daily based on blood pressure response.
Patients with renal impairment and haemodialysis patients:
No initial dosage adjustment is necessary in patients with renal impairment or in haemodialysis patients.
Patients with hepatic impairment:
A lower dose should be considered for patients with a history of hepatic impairment. Other preparations with appropriate strength of losartan should be administered. There is no therapeutic experience in patients with severe hepatic impairment. Therefore, losartan is contraindicated in patients with severe hepatic impairment.
Elderly:
Agilosart 100 is not suitable to initiate the treatment for elderly patients (> 75 years).
Administration: Losartan may be administered with or without food.

Contraindications

Hypersensitivity to losartan or any excipients of the drug.
Pregnant women.
Patients with liver failure.
Patients with kidney failure having blood creatinine levels ≥ 250 mmol / l or Potassium in the blood ≥ 5 mmol / l or creatinine clearance ≤ 30 mmol/l/min.

Warnings and precautions for use

Special monitoring and/or dose reduction should be considered in patients with volume depletion, being treated with diuretics and patients with other factors that may lead to hypotension. Patients with either unibilateral or bilateral renal artery stenosis, or stenosis of the artery to a solitary kidney are also at increased risk of unwanted effects (elevated creatinine and urea) and the treatment should be monitored closely.
Because of the risk of hyperkalemia, blood potassium levels should be monitored in elderly and patients with renal impairment. Do not use with potassium-sparing diuretics. The concomitant use of potassium sparing diuretics with losartan is not recommended.
Patients with liver failure have to take lower doses.
Hypersensitivity reactions:
Angiooedema: Patients with a history of angiooedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored.
Hypotension and Electrolyte/Fluid Imbalance:
Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of losartan potassium film-coated tablets, or a lower starting dose should be used. 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 treated. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalemia was higher in the group treated with losartan potassium film-coated tablets as compared to the placebo group. 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 30-50ml/min should be closely monitored.
The concomitant use of potassium sparing diuretics, potassium supplements and potassium containing salt substitutes with losartan is not recommended.
Hepatic 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. Losartan is also not recommended in children with hepatic impairment.
Renal impairment:
Because of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the rennin angiotensin aldosterone system such as those with severe cardiac insufficiency or pre-existing renal dysfunction). 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 <30ml/min/1.73m2 as no data are available.
Renal function should be regularly monitored during treatment with losartan as the drug may worsen the condition of renal impairment. This applies particularly when losartan 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.
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 product acting through inhibition of the renin-angiotensin system. Therefore, the use of losartan tablets is not recommended.
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:
In patients with heart failure, with or without renal impairment, as with other medicinal product acting on the renin-angiotensin system, there is 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.
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:
AIIRAs should not be initiated during pregnancy. Unless continued AIIRAs 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 AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
Dual blockade of the renin-angiotensin-aldosterone system:
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). So dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Other warnings and precautions:
As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.
Lactose:
This medicine contains lactose. Patients with rare genetic abnormalities of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not be used.

Recommendation for pregnancy and breastfeeding

Pregnancy:
When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause oligohydramnios, hypotension, anuria, oliguria, fetal craniofacial deformation and even death to the developing fetus. Although losartan use during the first trimester of pregnancy has not been found to be related to the fetal risk, when pregnancy is detected, losartan should be stopped as soon as possible.
Lactation:
It is not known whether losartan is excreted in human milk, because of potential adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Effects on ability to drive and use machines

As other antihypertensive drugs, caution should be taken when driving a vehicle and operating machines because losartan may cause headache, dizziness, fatigue, especially at the beginning of treatment or when the dose is increased.

Interactions, incompatibilities of medicine

Losartan does not affect the pharmacokinetics of oral or intravenous digoxin.
Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite.
Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite.
Coadministration of losartan and potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium.
Rifampicin, aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenytoin, may reduce the concentration of losartan and its plasma metabolites when concomitantly administered.
Losartan increases the effect of amifostine, antihypertensive drugs, carvedilol, hypoglycemic agents, lithium, potassium-sparing diuretics, rituximab.
There is no pharmacokinetic interaction between losartan and hydrochlorothiazide.
Nonsteroidal anti-inflammatory drugs (NSAIDs), especially COX-2, combined with losartan may cause kidney failure, so renal function should be monitored.

Undesirable effects (ADRs)

Most side effects are mild and may go away on their own over time.
Common, ADR > 1/100
Cardiovascular: Hypotension, chest pain.
Nervous system: Insomnia, dizziness, fatigue.
Endocrine – metabolic: Hypoglycaemia, hyperkalaemia.
Digestive: Diarrhea, dyspepsia.
Hematologic: Small decreases in hemoglobin and hematocrit.
Musculoskeletal: Back pain, leg pain, muscle pain.
Renal: Decreased serum uric acid levels (at high doses), urinary tract infections.
Respiratory: Cough (less likely to cause an uncontrollable cough than ACE inhibitors), nasal congestion, sinusitis.
Uncommon: 1/1000 < ADR < 1/100
Cardiovascular: Orthostatic hypotension, chest pain, second degree AV block, palpitations, sinus bradycardia, tachycardia, facial edema, flushing.
Nervous system: Anxiety, ataxia, confusion, depression, migraine, sleep disorder, fever, vertigo. Skin: Alopecia, dermatitis, dry skin, erythema, photosensitivity, pruritus, urticaria, bruising, rash.
Endocrine – metabolic: Gout.
Digestive: Anorexia, constipation, flatulence, vomiting, loss of appetite, gastritis.
Urogenital: Impotence, decreased libido, urinary frequency, nocturia.
Liver: Mild elevations of liver enzymes and serum bilirubin.
Neuromuscular-skeletal: Paresthesia, tremor, musculoskeletal pain, muscle weakness, joint swelling, myalgia.
Eyes: Blurred vision, conjunctivitis, decreased vision, burning/stinging in the eye.
Ears: Tinnitus.
Kidneys: Urinary tract infections, mild increase of urea or creatinine in urine.
Respiratory: Dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.
Other effects: Sweating.

Overdose and management

Limited data are available regarding overdosage in humans.
The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia may also be found resulting from parasympathetic (vagal) stimulation.
If symptomatic hypotension occurs supportive treatment should be applied. Neither losartan nor its active metabolite can be removed by hemodialysis.

Pharmacodynamic properties

Losartan potassium, an angiotensin II receptor antagonist (Type AT1), is the first of a new class of agents to be introduced for the treatment of hypertension.
Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex.
Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. Losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor. Angiotensin II antagonists and ACE inhibitors also have similar hemodynamic effects, but angiotensin II antagonists have no popular adverse effect of ACE inhibitors, that is dry cough.

Pharmacokinetic properties

Following oral administration, losartan is well absorbed and undergoes substantial first-pass hepatic metabolism by cytochrome P450 enzymes (CYP2C9 và CYP3A4). Bioavailability of losartan is approximately 33%. Approximately 14% of the oral dose of losartan is converted to an active metabolite that is responsible for most of the angiotensin II receptor antagonism. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours. Mean peak 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 highly bound to plasma proteins (> 98%), primarily albumin, and they do not cross the blood-brain barrier. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. 35% of losartan dose is excreted in the urine and about 60% in the feces.
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 time higher than in young male volunteers.
Plasma concentrations of losartan are not altered in patients with a creatinine clearance above 10 ml/min.
Compared to patients with normal renal function, the AUC for losartan is about 2 times higher in haemodialysis dialysis 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 hypertensive paediatric patients> 1 month to < 16 years of age with oral administration of approximately 0.54 to 0.77 mg/kg of losartan, once daily (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, pre-school children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing pre-school children with adolescents these differences became statistically significant. Exposure in infants/toddlers was comparatively high.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.