LOSARTAN POTASSIUM LICONSA 100 MG FILM-COATED TABLETS

Active substance: LOSARTAN POTASSIUM

View full screen / Print PDF » Download PDF ⇩

Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Losartan potassium Liconsa 100 mg Film-coated Tablets
Losartan potassium 100 mg Film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Losartan potassium Liconsa 100mg Tablet contains 100mg of losartan
(as potassium salt)
Each Losartan potassium Liconsa 100mg tablet contains 51.0mg lactose
monohydrate
For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Film-coated tablets
Losartan potassium Liconsa 100mg tablet
White, round film-coated tablets

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
• Treatment of essential hypertension.
• Treatment of renal disease in patients with hypertension and type 2 diabetes
mellitus with proteinuria >0.5g/day as part of an antihypertensive
treatment.
• Treatment of chronic heart failure (in patients >60 years), when treatment
with 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 stabilised under the treatment of the chronic heart failure.
• Reduction in the risk of stroke in hypertensive patients with left ventricular
hypertrophy documented by ECG (see section 5.1 LIFE study, Race).

4.2

Posology and method of administration
Losartan tablets should be swallowed with a glass of water.
Losartan potassium Liconsa may be administered with or without food.
Hypertension

The usual starting and maintenance dose is 50mg 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 100mg once daily (in the morning).
Losartan potassium Liconsa may be administered with other antihypertensive
agents, especially with diuretics (e.g. hydrochlorothiazide).
Paediatric hypertension
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 (see 5.1:
Pharmacodynamic properties). Limited pharmacokinetic data are available in
hypertensive children above one month of age (see 5.2: Pharmacokinetic
properties).
For patients who can swallow tablets, the recommended dose is 25mg once
daily in patients >20 to <50kg. In exceptional cases the dose can be increased
to a maximum of 50mg once daily. Dosage should be adjusted according to
blood pressure response.
In patients >50kg, the usual dose is 50mg once daily. In exceptional cases the
dose can be adjusted to a maximum of 100mg once daily. Doses above
1.4mg/kg (or in excess of 100mg) 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 < 30ml/ 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).
Hypertensive type II diabetic patients with proteinuria > 0.5g/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 after
initiation of therapy onwards. Losartan potassium Liconsa 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 potassium Liconsa in patients with heart
failure is 12.5mg once daily. The dose should generally be titrated at weekly
intervals (i.e. 12.5mg daily, 25mg daily, 50mg daily) to the usual maintenance
dose of 50mg once daily, as tolerated by the patient.
The 12.5mg-strength is not realizable with Losartan potassium Liconsa and
therefore other medicinal products should be used for this dosage.
Reduction in the risk of stroke in hypertensive patients with left ventricular
hypertrophy documented by ECG
The usual starting dose is 50mg of Losartan potassium Liconsa once daily. A
low dose of hydrochlorothiazide should be added and/ or the dose of Losartan
potassium Liconsa should be increased to 100mg once daily based on blood
pressure response.

Use in patients with intravascular volume depletion:
For patients with intravascular volume-depletion (e.g. those treated with highdose diuretics), a starting dose of 25mg 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).
Use in Elderly
Although consideration should be given to initiating therapy with 25mg in
patients over 75 years of age, dosage adjustment is not usually necessary for
the elderly.
4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section
4.4 and 6.1).
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Severe hepatic impairment

4.4

Special warnings and precautions for use

Hypersensitivity
Angiooedema. Patients with a history of angiooedema (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,
diarrhoea 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 hyperkalemia was higher in the group treated with losartan
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 30-50 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 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 also 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 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 pediatric patients with renal impairment
Losartan is not recommended in children with glomerular filtration rate < 30ml/ min/ 1.73
m2as 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 product 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 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.

Excipients
This medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.

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.

4.5

Interaction with other medicinal products and other forms of interaction

Other antihypertensive agents may increase the hypotensive action of Losartan. Concomitant
use with other substances which may induce hypotension an adverse reaction (like tricyclic
antidepressants, antipsychotics, baclofene, and amifostine), may increase the risk of
hypotension.
Losartan is predominantly metabolised 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 rifampicine (inducer of matabolism
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
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 renin-angiotensin-aldosterone system
agent.

4.6

Fertility, pregnancy and lactation

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 second and third trimesters of
pregnancy (see sections 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 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.
Exposure to AIIRAs 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 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 sections 4.3 and 4.4).
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 breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7

Effects on ability to drive and use machines
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.

4.8

Undesirable effects

Losartan has been evaluated in clinical studies as follows:
in a controlled clinical trials in > 3000 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 > 9000 hypertensive patients 55 to 80 years of age with
left ventricular hypertrophy
in a controlled clinical trial in > 7700 adult patients with chronic heart failure
in a controlled clinical trial in > 1500 type 2 diabetic patients 31 years of age and older
with proteinuria
In these clinical trials, the most common adverse reaction was dizziness.

The frequency of adverse events 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
In controlled clinical trials in 3300 adults patients 18 years fo age and older with essential
hypertension the following adverse events were reported
System organ class
Nervous system disorders
Cardiac disorder
Vascular disorders

Gastrointestinal disorders
General
disorders
administration site conditions
Investigations

Adverse reaction
dizziness, vertigo
somnolence, headache, sleep disorders
palpitations, angina pectoris
symptomatic hypotension (especially in
patients
with
intravascular
volume
depletion, e.g. patients with severe heart
failure or under treatment with high dose
diuretics), dose-related orthostatic effects,
rash
abdominal pain, obstipation
and asthenia, fatique, oedema

hyperkalemia
increased alanine aminotransferase (ALT)*
* usually resolved upon discontinuation

Frequency
common
uncommon
uncommon
uncommon

uncommon
uncommon
common
rare

Hypertensive patients with left ventricular hypertrophy
In a controlled clinical trial in 9193 hypertensive patients 55 to 80 years of age, with left
ventricular hypertrophy, the following adverse reactions were reported:
System organ class
Nervous system disorders
Ear and labyrinth disorders

Adverse reaction
dizziness
vertigo

General
disorders
and asthenia, fatique
administration site conditions

Frequency
common
common
common

Chronic heart failure
In a controlled clinical trial in patients with chronic heart failure (see ELITE I, ELITE II, and
HEAAL study, section 5.1) the following adverse reactions were reported:
System organ class
Nervous system disorders

Adverse reaction
dizziness
headache
paraesthesia
syncope, atrial fibrillation, cerebrovascular
accident
hypotension, including orthostatic hypotension

Cardiac disorder
Vascular disorders
Blood and lymphatic system
disorders
Respiratory,
thoracic
and
mediastinal disorders
Gastrointestinal disorders
Skin and subcutaneous tissue
disorders
General
disorders
and
administration site conditions
Investigations

Frequency
common
uncommon
rare
rare
common

anaemia

common

dyspnoea, cough

uncommon

diarrhoea, nausea, vomiting
urticaria, pruritus, rash

uncommon
uncommon

asthenia, fatique

uncommon

increase in blood urea, serum creatinine and common
serum potassium
nutrition hyperkalaemia
uncommon*

Metabolism
and
disorders
Renal and urinary disorders
renal impairment, renal failure
* common in patients who received 150 mg losartan instead of 50 mg losartan

common

Hypertension and type 2 diabetes with renal disease
In a controlled clinical trial in 1513 type 2 diabetic patients 31 years of age and older, with
proteinuria (RENAAL study, see section 5.1), the most common drug-related adverse
reactions which were reported for losartan are as follows:
System organ class
Nervous system disorders
Vascular disorders

Adverse reaction
dizziness
hypotension

Frequency
common
common

General
disorders
and asthenia, fatique
common
administration site conditions
Investigations
hypoglycaemia, hyperkalaemia*
common
*In a clinical study conducted in type 2 diabetic patients with nephropathy, 9.9% of patients
treated with Losartan tablets developed hyperkalaemia >5.5 mmol/l and 3.4% of patients treated with
placebo

The following adverse reactions occurred more often in patients receiving losartan than
placebo:
System organ class
Blood and lymphatic
disorders
Cardiac disorder

Adverse reaction
system anaemia
syncope, palpitations

Frequency
not known
not known

Vascular disorders

orthostatic hypotension

not known

Gastrointestinal disorders
diarrhoea
Muscoskeletal and connective back pain
tissue disorders:

not known
not known

Renal and urinary disorders
urinary tract infections
General
disorders
and flu-like symptoms
administration site conditions

not known
not known

Post-marketing experience
The following adverse reactions have been reported in post-marketing experience:
System organ class
Blood and lymphatic system
disorders
Ear and labyrinth disorders
Immune system disorders

Nervous system disorders
Respiratory,
thoracic
mediastinal disorders:

Adverse reaction
anaemia, thrombocytopenia

Frequency
not known

Tinnitus
not known
hypersensitivity:
anaphylactic
reactions, rare
angiooedema including swelling of the larynx
and glottis causing airway obstruction and/or
swelling of the face, lips, pharynx, and/or
tongue; in some of these patients angiooedema
had been reported in the past in connection with
the administration of other medicines, including
ACE inhibitors; vasculitis, including HenochSchonlein purpura
migraine
not known

and Cough

Gastrointestinal disorders
diarrhoea, pancreatitis
General
disorders
and malaise
administration site conditions
Hepatobiliary disorders
hepatitis
liver function abnormalities
Skin and subcutaneous tissue urticaria, pruritus, rash, photosensitivity
disorders
Muscoskeletal and connective myalgia, arthralgia, rhabdomyolysis
tissue disorders:

not known

not known
not known
rare
not known
not known
not known

Reproductive system and breast erectile dysfunction/impotence
disorders
Psychiatric disorders
depression

not known

Investigations

not known

Renal and urinary disorders:

hyponatraemia

not known

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 experience profile for pediatric patients appears to be similar to that seen in adult
patients.
Data in the pediatric population are limited.

4.9

Overdose

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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II Receptor Antagonists, ATC code:
C09CA01
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
bradykininmediated 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 postdose.
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 leftventricular hypertrophy. Patients were randomised to once daily Losartan
50mg or once daily atenolol 50mg. If goal blood pressure (<140/90mmHg)
was not reached, hydrochlorothiazide (12.5mg) was added first and, if needed,
the dose of Losartan or atenolol was then increased to 100mg 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 Liconsa over and above the benefit of a blood lowering
pressure.
Patients with proteinuria and a serum creatinine of 1.3 – 3.0mg/dl were
randomised to receive Losartan 50mg 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 100mg daily as
appropriate; 72 % of patients were taking the 100mg daily dose for the
majority of the time. Other antihypertensive agents (diuretics, calcium
antagonists, alpha- and beta-receptor 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 events that was comparable to the
placebo group.

ELITE I and ELITE II Study
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 50mg once daily (starting dose 12.5mg,
increased to 25mg, then 50mg once daily) was compared with captopril 50mg
three times daily (starting dose 12.5mg, increased to 25mg and then to 50mg
three times daily). The primary endpoint of this prospective study was the allcause 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 events 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 Hypertension
The antihypertensive effect of Losartan potassium Liconsa was established in
a clinical study involving 177 hypertensive paediatric patients 6 to 16 years of
age with a body weight >20kg and a glomerular filtration rate
>30ml/min/1.73m2. Patients who weighted >20kg to <50kg received either
2.5, 25 or 50mg of losartan daily and patients who weighted >50kg received
either 5, 50 or 100mg 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: -6.2mmHg vs. -11.65mmHg), but was attenuated when comparing the
middle dose group with the high dose group (period I: -11.65mmHg vs. 12.21mmHg). The lowest doses studied, 2.5mg and 5mg, corresponding to an
average daily dose of 0.07mg/kg, did not appear to offer consistent
antihypertensive efficacy.
These results were confirmed during period II of the study where patients were
randomized 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 (6.70mm Hg middle dose vs. 5.38mmHg 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.

5.2

Pharmacokinetic properties
Absorption
Following oral administration, losartan is well absorbed and undergoes firstpass 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-labeled Losartan potassium Liconsa, 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 600ml/min and
50ml/min, respectively. Renal clearance of losartan and its active metabolite is
about 74ml/min and 26ml/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
Liconsa doses up to 200mg.
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 100mg, neither
losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contributes to the elimination of losartan
and its metabolites.
Following an oral dose/intravenous administration of 14C-labeled 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 10ml/minute. 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 heamodialysis 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 0.77mg/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.

5.3

Preclinical safety data
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
gastrointestinal changes (mucous membrane lesions, ulcers, erosions,
haemorrhages). Like other substances that directly affect the renin-angiotensin
system, losartan has been shown to induce adverse effects on the late foetal
development, resulting in foetal death and malformations.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Each tablet contains the following inactive ingredients:
Core:
- Lactose monohydrate
- Pregelatinised maize starch
- Microcrystalline cellulose
- Magnesium stearate
Coating:

- Hyprolose
- Hypromellose
- Titanium dioxide (E171)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
30 months

6.4

Special precautions for storage

No special storage conditions are required

6.5

Nature and contents of container
Losartan potassium Liconsa 100mg - PVC/PE/PVDC blister packages with
aluminium foil lidding in packs of 7, 10, 14, 15, 21, 28, 30, 50, 56, 98, 100,
210 or 280 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
LABORATORIOS LICONSA, S.A.
Gran Vía Carlos III, 98, 7th floor, 08028 Barcelona
SPAIN

8

MARKETING AUTHORISATION NUMBER(S)
PL 23218/0003

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/02/2011

10

DATE OF REVISION OF THE TEXT

17/12/2013

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide
(web1)