• 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.
• Treatment of chronic heart failure in adult patients when treatment with Angiotensin
converting enzyme (ACE) inhibitors is not considered suitable due to incompatibility,
especially cough, or contraindication. Patients with heart failure who have been stabilised with
an ACE inhibitor should not be switched to losartan. The patients should have a left ventricular
ejection fraction 40% and should be clinically stable and on an established treatment regimen
for chronic heart failure.
• Reduction in the risk of stroke in adult hypertensive patients with left ventricular hypertrophy
documented by ECG (see section 5.1 LIFE study, Race).

Posology
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).

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) 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 section 4.4).
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 sections 4.3 and 4.4).
Paediatric population
There are limited data on the efficacy and safety of losartan in children and adolescents aged 6-
18 years old for the treatment of hypertension (see section 5.1). Limited pharmacokinetic data
are available in hypertensive children above one month of age (see section 5.2).
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 (see also section 4.4).
Losartan is also not recommended in children with hepatic impairment (see also section 4.4).
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.
Method of administration
Losartan tablets should be swallowed with a glass of water.
Losartan tablets may be administered with or without food.

Hypersensitivity
Angio-oedema. Patients with a history of angio-oedema (swelling of the face, lips, throat,
and/or tongue) should be closely monitored (see section 4.8).
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 section 4.2). 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 hyperkalaemia was higher in the group treated with losartan as
compared to the placebo group (see section 4.8). 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 potassiumcontaining
salt substitutes with
losartan is not recommended (see section 4.5).
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 sections 4.2, 4.3 and 5.2).
Losartan is not recommended in children with hepatic impairment (see section 4.2).
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 reninangiotensin- 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 section 4.2).
Renal function should be regularly monitored during treatment with losartan as it may
deteriorate. 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 (see section 4.5).
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 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, 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 lifethreatening 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 section 5.1).
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
Losartan should not be initiated during pregnancy. Unless continued losartan therapy 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 4.6).
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.

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 metabolised by cytochrome P450 (CYP) 2C9 to the active carboxyacid
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.
Comedication 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
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.
Dual blockade (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist)
should be limited to individually defined cases with close monitoring of renal function. Some
studies have shown that in patients with established atherosclerotic disease, heart failure, or
with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone
system is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and
changes in renal function (including acute renal failure) as compared to use of a single reninangiotensin-
aldosterone system agent.

Pregnancy
The use of losartan is not recommended during the first trimester of pregnancy (see section
4.4). The use of losartan is contraindicated during the 2nd and 3rd trimester of pregnancy (see
section 4.3 and 4.4).
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, hyperkalaemia) (see also section 5.3). 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
also section 4.3 and 4.4).
Breastfeeding
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.

No studies on the effects on the ability to drive and use machines have been performed.
However, when driving vehicles or operating machinery it must be borne in mind that
dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in
particular during initiation of treatment or when the dose is increased.

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 paediatric 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
• In controlled clinical trials in > 7,700 adult patients with chronic heart failure
• In a controlled clinical trial in > 1,500 type 2 diabetic patients 31 years of age and older with
proteinuria
In these clinical trials, the most common adverse event was dizziness.
The frequency of adverse reactions listed below 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).
Hypertension

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 section 4.4).
Paediatric population
The adverse reaction profile for paediatric patients appears to be similar to that seen in adult
patients. Data in the paediatric population are limited.

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. Stabilisation 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 haemodialysis.

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. Measurements 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 effects 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
randomised, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80
years with ECG-documented left-ventricular hypertrophy. Patients were randomised 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 antihypertensives, 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 randomised 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 betareceptor blockers and
also centrally acting antihypertensives) 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.
HEAAL Study
The Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study
was a controlled clinical study conducted worldwide in 3834 patients aged 18 to 98 years with
heart failure (NYHA Class II-IV) who were intolerant of ACE inhibitor treatment. Patients
were randomised to receive losartan 50 mg once a day or losartan 150 mg, on a background of
conventional therapy excluding ACE-inhibitors.
Patients were followed for over 4 years (median 4.7 years). The primary endpoint of the study
was a composite endpoint of all cause death or hospitalisation for heart failure.
The results showed that treatment with 150 mg losartan (828 events) as compared with 50 mg
losartan (889 events) resulted in a 10.1% risk reduction (p=0.027 95% confidence interval
0.82-0.99) in the number of patients reaching the primary composite endpoint. This was mainly
attributable to a reduction of the incidence of hospitalisation for heart failure. Treatment with
150 mg losartan reduced the risk of hospitalisation for heart failure by 13.5% relative to 50 mg

losartan (p=0.025 95% confidence interval 0.76-0.98). The rate of all cause death was not
significantly different between the treatment groups. Renal impairment, hypotension, and
hyperkalaemia were more common in the 150 mg group than in the 50 mg group, but these
adverse events did not lead to significantly more treatment discontinuations in the 150 mg
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) in order 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 on the basis of a
significantly lower rate of discontinuations of therapy on 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.
Paediatric Population
Paediatric Hypertension
The antihypertensive effect of losartan was established in a clinical study involving 177
hypertensive paediatric patients 6 to 16 years of age with a body weight > 20 kg and a
glomerular filtration rate > 30 ml/min/1.73 m2. Patients who weighed > 20 kg to < 50 kg
received either 2.5, 25 or 50 mg of losartan daily and patients who weighed > 50 kg received
either 5, 50 or 100 mg of losartan daily. At the end of three weeks, losartan administration once
daily lowered trough blood pressure in a dose-dependent manner.
Overall, there was a dose-response. The dose-response relationship became very obvious in the
low dose group compared to the middle dose group (period I: -6.2 mmHg vs. -11.65 mmHg),
but was attenuated when comparing the middle dose group with the high dose group (period I:

-11.65 mmHg vs. -12.21 mmHg). The lowest doses studied, 2.5 mg and 5 mg, corresponding to
an average daily dose of 0.07 mg/ kg, did not appear to offer consistent antihypertensive
efficacy.
These results were confirmed during period II of the study where patients were randomised to
continue losartan or placebo, after three weeks of treatment. The difference in blood pressure
increase as compared to placebo was largest in the middle dose group (6.70 mmHg middle
dose vs. 5.38 mmHg high dose). The rise in trough diastolic blood pressure was the same in
patients receiving placebo and in those continuing losartan at the lowest dose in each group,
again suggesting that the lowest dose in each group did not have significant antihypertensive
effect.
Long-term effects of losartan on growth, puberty and general development have not been
studied. The long-term efficacy of antihypertensive therapy with losartan in childhood to
reduce cardiovascular morbidity and mortality has also not been established.
In hypertensive (N=60) and normotensive (N=246) children with proteinuria, the effect of
losartan on proteinuria was evaluated in a 12-week placebo- and active-controlled (amlodipine)
clinical study. Proteinuria was defined as urinary protein/creatinine ratio of ≥0.3. The
hypertensive patients (ages 6 through 18 years) were randomised to receive either losartan
(n=30) or amlodipine (n=30). The normotensive patients (ages 1 through 18 years) were
randomised to receive either losartan (n=122) or placebo (n=124). Losartan was given at doses
of 0.7 mg/kg to 1.4 mg/kg (up to maximum dose of 100 mg per day). Amlodipine was given at
doses of 0.05 mg/kg to 0.2 mg/kg (up to a maximum dose of 5 mg per day).
Overall, after 12 weeks of treatment, patients receiving losartan experienced a statistically
significant reduction from baseline in proteinuria of 36% versus 1% increase in
placebo/amlodipine group (p ≤0.001). Hypertensive patients receiving losartan experienced a
reduction from baseline proteinuria of -41.5% (95% CI -29.9;-51.1) versus +2.4% (95% CI -
22.2;14.1) in the amlodipine group. The decline in both systolic blood pressure and diastolic
blood pressure was greater in the losartan group (- 5.5/-3.8 mmHg) versus the amlodipine
group (-0.1/+0.8 mm Hg). In normotensive children a small decrease in blood pressure was
observed in the losartan group (-3.7/-3.4 mm Hg) compared to placebo. No significant
correlation between the decline in proteinuria and blood pressure was noted, however it is
possible that the decline in blood pressure was responsible, in part, for the decline in
proteinuria in the losartan treated group.
Long-term effects of losartan in children with proteinuria were studied for up to 3 years in the
open-label safety extension phase of the same study, in which all patients completing the 12-
week base study were invited to participate. A total of 268 patients entered the open-label
extension phase and were re-randomized to losartan (N=134) or enalapril (N=134) and 109
patients had ≥3 years of follow-up (pre-specified termination point of ≥100 patients completing

3 years of follow-up in the extension period). The dose ranges of losartan and enalapril, given
according to investigator discretion, were 0.30 to 4.42 mg/kg/day and 0.02 to 1.13 mg/kg/day,
respectively. The maximum daily doses of 50 mg for <50 kg body weight and 100 mg >50 kg
were not exceeded for most patients during the extension phase of the study. For normotensive
patients (n=205), enalapril had a numerically greater effect compared to losartan on proteinuria
(-33.0% (95%CI -47.2;-15.0) vs -16.6% (95%CI -34.9; 6.8)) and on GFR (9.4(95%CI 0.4;
18.4) vs -4.0(95%CI -13.1; 5.0) ml/min/1.73m2)). For hypertensive patients (n=49), losartan
had a numerically greater effect on proteinuria (-44.5% (95%CI -64.8; -12.4) vs -39.5%
(95%CI -62.5; -2.2)) and GFR (18.9(95%CI 5.2; 32.5) vs -13.4(95%CI -27.3; 0.6))
ml/min/1.73m2.
In summary, the results of the safety extension show that losartan was well-tolerated and led to
sustained decreases in proteinuria with no appreciable change in glomerular filtration rate
(GFR) over 3 years.

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 1% 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 (see section 4.2 and 4.4).
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.

Preclinical data reveal no special hazard for humans based on conventional studies of general
pharmacology, genotoxicity and carcinogenic potential. In repeated dose toxicity studies, the
administration of losartan induced a decrease in the red blood cell parameters (erythrocytes,
haemoglobin, haematocrit), a rise in urea-N in the serum and occasional rises in serum

creatinine, a decrease in heart weight (without a histological correlate) and gastro-intestinal
changes (mucous membrane lesions, ulcers, erosions, haemorrhages). Like other substances
that directly affect the renin-angiotensin system, losartan has been shown to induce adverse
reactions on the late foetal development, resulting in foetal death and malformations.

Excipients:
Microcrystalline Cellulose
Croscarmellose Sodium Type A
Colloidal Silicon Dioxide
Purified Talc
Magnesium Stearate
Coating Materials:
Polysorbate 80
Titanium Dioxide
Purified Talc
Polyethylene Glycol MW 6000
Hydroxypropyl Methylcellulose
Purified Water

Not Applicable.

Store below 30°C.

30/pack
Reel PVC/PVDC and aluminium foil lid

No Special Disposal