Essential hypertension.

The recommended dose is 600 mg once daily.
In most patients, the maximum blood pressure-lowering effect is reached 2 to 3 weeks after
starting the therapy.
Eprosartan can be used as a monotherapy or in combination with other antihypertensives (see
sections 4.3, 4.4, 4.5 and 5.1). Thiazide diuretics in particular, such as hydrochlorothiazide or
calcium channel-blocking agents, have been found to have an additive effect on eprosartan.
Eprosartan can be taken with or without food.
Elderly patients
In elderly patients, the dosage does not have to be adjusted.
Dosage in hepatically impaired patients
Adjustment of the dose is not required in patients with mild to moderate hepatic impairment.
Eprosartan is contraindicated in patients with severe hepatic impairment (see section 4.3.)
Dosage in renally impaired patients
In patients with moderate to severe renal impairment (creatinine clearance < 60 ml/min.), the
daily dosage should not exceed 600 mg.

 

• Hypersensitivity to the active substance or to any of the excipients indicated in section 6.1. • Second and third trimester of pregnancy (see sections 4.4 and 4.6). • Severe hepatic impairment. • Haemodynamically significant bilateral renovascular disease or severe stenosis in a single functioning kidney. • The concomitant use of Teveten with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Hepatic impairment
Caution is advised if eprosartan is used in patients with mild to moderate hepatic impairment,
because there is only limited experience with this patient group.
Renal impairment
In patients with moderate to severe renal impairment (creatinine clearance < 60 ml/min.), the
daily dosage should not exceed 600 mg. Caution is advised when used by patients with
creatinine clearance < 30 ml/min and by patients undergoing dialysis.
Eprosartan is contraindicated in patients with severe unilateral or bilateral renal artery stenosis
(see section 4.3). In the case of impaired renal function, e.g. as a result of renal artery stenosis,
acute deterioration of renal function should be taken into account. In such patients, it is advisable
to monitor renal function during the treatment.
Caution is advised in patients undergoing haemodialysis. There is no experience with
administration of eprosartan in patients who have recently had a kidney transplant.

Patients at risk of renal impairment
Some patients whose renal function is dependent on the constant inherent activity of the reninangiotensin-
aldosterone system (e.g. patients with severe cardiac failure [NYHA classification:
class IV], bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney), run
the risk of developing oliguria and/or progressive azotaemia and in rare cases acute kidney
failure during treatment with an angiotensin-converting enzyme (ACE)-inhibitor. Patients who
are being treated concomitantly with a diuretic have a greater chance of acquiring these
symptoms. In patients who are sensitive to this, there is insufficient therapeutic experience with
angiotensin-II receptor blockers, such as eprosartan, to determine whether there is a comparable
risk of compromising renal function. If eprosartan is used in patients with impaired renal
function, before starting the treatment with eprosartan and also at intervals during the therapy,
renal function should be evaluated. If, during the therapy, worsening of renal function is noted,
the treatment with eprosartan should be reconsidered.

Based on experience with other drugs of this class and ACE inhibitors, the following general
precautions apply:

Hyperkalaemia

During treatment with other drugs that act on the renin-angiotensin-aldosterone system,
hyperkalaemia can occur. This applies in particular to patients with impaired renal function
and/or heart failure. In patients at risk, careful monitoring of serum potassium is recommended.

Based on experience with other drugs that act on the renin-angiotensin-aldosterone system,
concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing
salt substitutes or other drugs that can increase serum potassium (e.g. heparin) leads to
increased serum potassium. A combination of these drugs with eprosartan should therefore be
used with caution.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that in case of concomitant use of ACE inhibitors, angiotensin II receptor
antagonists or aliskiren the risk of hypotension, hyperkalaemia and a reduced renal function
(including acute renal failure) increases. Dual blockade of RAAS by the combined use of ACE
inhibitors, angiotensin II receptor antagonists or aliskiren is therefore not recommended (see
sections 4.5 and 5.1).
If treatment with dual blockade is considered absolutely necessary, this may only be carried out
under specialist supervision and the renal function, electrolytes and blood pressure should be
checked regularly.
ACE inhibitors and angiotensin II receptor antagonists should not be taken simultaneously by
patients with diabetic nephropathy.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with eprosartan.

Hypotension
In patients with severe sodium and/or volume depletion (for example when high doses of
diuretics are administered), symptomatic hypotension can occur after starting eprosartan
therapy. Sodium and/or volume depletion should be corrected before commencing the
eprosartan treatment, or the set dose of diuretics should be reduced.
Coronary heart disease
There is limited experience in patients with coronary heart disease.
Aortic and mitral valve stenosis and hypertrophic cardiomyopathy
As applies to all vasodilators, eprosartan should be used with caution in patients with aortic and
mitral valve stenosis or hypertrophic cardiomyopathy.

Pregnancy
Therapy with angiotensin II receptor antagonists should not be initiated during pregnancy.
Patients who are planning pregnancy should be changed to an alternative antihypertensive
therapy with a known safety profile for use during pregnancy, unless continuation of the
treatment with angiotensin II receptor antagonists is considered necessary. If pregnancy is
diagnosed, the treatment with an angiotensin II receptor antagonist should be stopped
immediately and, if necessary, an alternative therapy should be started (see sections 4.3 and
4.6).
Other warnings and precautionary measures
As is seen with angiotensin-converting enzyme inhibitors, eprosartan and the other angiotensin
II receptor antagonists lower blood pressure in negroid people clearly less effectively than in
non-negroid people, possibly because of a higher prevalence of low renin in the negroid
hypertensive population.

Lactose

Patients with rare hereditary disorders, such as galactose intolerance, Lapp lactase deficiency or
glucose-galactose malabsorption, should not use this medicinal product.

Based on placebo-controlled clinical studies in which a significantly increased serum potassium
concentration was observed, and based on experience with the use of other medicinal products
that influence the renin-angiotensin-aldosterone system, concomitant use of potassium-sparing
diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that can
increase serum potassium levels (e.g. heparin) can lead to increased serum potassium.
The data from clinical studies show that dual blockade of the renin-angiotensin-aldosterone
system (RAAS) in case of the combined use of ACE inhibitors, angiotensin II receptor
antagonists and aliskiren, is connected with a higher frequency of undesirable effects such as
hypotension, hyperkalaemia and a reduced renal function (including acute renal failure)
compared with the use of a single medicinal product that works on the RAAS (see sections 4.3,
4.4 and 5.1).

The antihypertensive effect can be intensified by other antihypertensives.
Toxicity and reversible increases in serum lithium concentrations have been reported during
concomitant use of lithium-containing medicinal products and ACE inhibitors. The possibility
of a similar effect after using eprosartan cannot be excluded and careful monitoring of the
lithium serum concentrations is recommended during concomitant use.
In vitro studies have shown that eprosartan does not inhibit the cytochrome P450 enzymes
CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E and 3A.

As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists with NSAIDs
(non-steroidal anti-inflammatory drugs [e.g. COX-2 inhibitors, acetylsalicylic acid (>3 g/daily)
and non-selective NSAIDs]) may lead to an increased risk of renal function deterioration,
including possible acute renal failure and an increase in serum potassium, especially in patients
who already have impaired renal function. Caution is advised when administering this
combination, particularly in the elderly. Patients should be adequately hydrated and monitoring of
renal function should be considered both after commencement of the combination therapy and
periodically thereafter.
Concomitant use of losartan with the NSAID indomethacin has led to reduced effectiveness of the
angiotensin II receptor antagonist; a class effect cannot be excluded.

Pregnancy
The use of angiotensin II receptor antagonists is not recommended during the first trimester of
pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated
during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
No clear conclusions can be drawn from the results of epidemiological investigation of the risk
of teratogenic effects as a consequence of exposure to angiotensin II receptor antagonists
during the first trimester of pregnancy; a slight increase in the risk can, however, not be
excluded. Although there are no controlled epidemiological data on the risk with angiotensin II
receptor antagonists, the risk may be comparable with this class of drugs. Patients who plan a
pregnancy should be changed to an alternative antihypertensive therapy with a known safety
profile for use during pregnancy, unless continuation of the treatment with an angiotensin II
receptor antagonist is considered necessary. If pregnancy is diagnosed, the treatment with

angiotensin II receptor antagonists should be stopped immediately and, if necessary, an
alternative therapy should be started.
It is known that exposure to angiotensin II receptor antagonists during the second and third
trimester can induce foetal toxicity (deteriorated renal function, oligohydramnios, skull
ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see
also section 5.3). If there has been exposure to angiotensin II receptor antagonists after the
second trimester of pregnancy, an ultrasound check of renal function and the skull is advised.
Neonates whose mothers have used angiotensin II receptor antagonists should be monitored
closely for hypotension (see also sections 4.3 and 4.4).

Lactation
Because no information is available on the use of Teveten during breastfeeding, Teveten is not
recommended and alternative treatments with a known safety profile are preferred for use during
breastfeeding, particularly when nursing a new-born or preterm infant.

The effect of eprosartan on the ability to drive and use machines has not been investigated, but
based on the pharmacological properties an effect is unlikely. When driving and using
machines, it should be borne in mind that when treating hypertension dizziness or fatigue may
occur.

The most commonly reported undesirable effects in patients treated with eprosartan are
headache and non-specific gastrointestinal disorders, which occur in approximately 11% and
8%, respectively, of patients.
The following undesirable effects have been reported in clinical trials, in which patients were
treated with eprosartan (n = 2316).
The undesirable effects are reported per system/organ class and according to their frequency.

Organ system	Very common ≥1/10	Common >1/100 - <1/10	Uncommon >1/1,000 - <1/100	Rare >1/10,000 - <1/1,000	Very rare <1/10,000 including isolated reports	Unknown, cannot be estimated from the available data
Immune system disorders			Hypersensitivity*
Metabolism and nutrition disorders		Hypertriglyceridaemia	Hyperkalaemia
Nervous system disorders	Headache*	Dizziness*, Fatigue, Depression
Cardiac disorders		Palpitations, Chest pain
Vascular disorders			Hypotension, including orthostatic hypotension
Respiratory, thoracic and mediastinal disorders		Rhinitis, Pharyngitis, Dyspnoea, Upper respiratory tract infection, Cough, Sinusitis, Bronchitis
Gastrointestinal disorders		Non-specific gastrointestinal system disorders (e.g. nausea, diarrhoea, vomiting), Abdominal pain, Dyspepsia
Hepatobiliary disorders					Impaired liver function
Skin and subcutaneous tissue disorders		Allergic skin reactions (e.g. rash, pruritus)	Angiooedema*			Facial swelling
Musculoskeletal and connective tissue disorders		Arthralgia, Myalgia, Backache
Renal and urinary disorders		Urinary tract infection				Impaired renal function including renal failure in patients at risk (e.g. renal artery stenosis)
General disorders and administration site conditions		Asthenia, Viral infection, Injury, Pain, Oedema
Investigations				Reduced haemoglobin count, Elevated blood urea nitrogen

*Did not occur at a higher frequency than the placebo

The following undesirable effects were reported spontaneously during post-marketing use of
eprosartan, in addition to the undesirable effects reported during clinical studies. Frequencies
cannot be estimated from the available data (unknown).
Renal and urinary disorders
Impaired renal function, including renal failure in patients at risk (e.g. renal artery stenosis).

Reporting suspected adverse drug reactions
It is important to report any suspected adverse drug reactions after authorisation of the
medicinal product. In this way the relationship between the benefits and risks of the medicinal
product can be constantly monitored. Healthcare professionals are asked to report all suspected
adverse drug reactions.

To report any side effect(s):
-National Pharmacovigilance Center (NPC)
o Fax: +966-1-205-7662
oCall NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
oToll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

 

Limited data are available on overdose in humans. There were individual post-marketing reports,
where dosages of up to 12,000 mg were taken. Most patients have not reported any symptoms.
One person suffered circulatory collapse after taking 12,000 mg of eprosartan. This person
recovered completely. The most likely manifestation of overdose is hypotension. The patient
should then be placed in a lying position, after which salt and fluid can be administered. The
treatment should be symptomatic and supportive. Depending on the time that has elapsed since
ingestion, the treatment may consist of induced vomiting, gastric lavage and/or administration of
activated carbon.
Eprosartan cannot be removed through haemodialysis.

Pharmacotherapeutic group: Angiotensin II (AT1) antagonists: ATC code: C09CA02.
Eprosartan is a potent, synthetic, orally active non-biphenyl tetrazole angiotensin II receptor
antagonist, which binds selectively to the AT1 receptor. Angiotensin II plays an important role
in the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor in many
tissues (e.g. smooth vascular musculature, adrenal glands, kidneys and heart) and activates
several important biological mechanisms, such as vasoconstriction, sodium retention and
release of aldosterone.
In healthy volunteers, eprosartan antagonised the effect of angiotensin II on blood pressure,
renal blood flow and the release of aldosterone. Whether eprosartan is now administered in a
single dose or in two half doses, it has a comparable effect on blood pressure in hypertensive

patients. This effect on blood pressure is maintained constant for a period of 24 hours. In
hypertensive patients, lowering of blood pressure did not cause any change in the heart rate.
In the MOSES study (morbidity and mortality after stroke, eprosartan compared with
nitrendipine for secondary prevention), 1,405 hypertensive patients with a history of
cerebrovascular events were treated with eprosartan or nitrendipine. In the eprosartan group,
78% of the patients received 600 mg once daily and 12% up to 800 mg daily; in the
nitrendipine group, 47% received 10 mg and 42% 20 mg daily (11% up to 40 mg) in a
prospective, randomised, open-label, blinded endpoint design. The defined primary endpoint
included mortality through all causes, cerebrovascular events (TIA, PRIND, stroke) and
cardiovascular events (unstable angina, myocardial infarction, heart failure, pulmonary
embolism and fatal cardiac dysrhythmia) including recurrent events. In both treatment arms, the
blood pressure objectives were achieved and maintained throughout the study. The primary
endpoint showed a significantly better result in the eprosartan group (21% risk reduction). The
numerical risk reduction was in the first analysis of the events 12% for the cerebrovascular
endpoints and 30% for the cardiovascular endpoints. These results were due in particular to a
reduction in the incidence of TIA/PRIND, unstable angina and heart failure. Overall mortality
was numerically in favour of nitrendipine; in the eprosartan group, 57 of the 681 patients died
versus 52 of 671 patients in the nitrendipine group (HR 1.07, 95% CI 0.73 - 1.56, p=0.725).
Fatal and non-fatal myocardial infarction occurred in 18 versus 20 patients and stroke in 36
versus 42 patients; numerically this is in favour of eprosartan. For the primary endpoint, the
effect of eprosartan seemed to be more pronounced in patients who were not given beta
blockers.

In hypertensive patients, eprosartan has no effect on fasting triglyceride, total cholesterol or
LDL cholesterol levels. In addition, eprosartan has no effect on fasting blood sugar levels.
Eprosartan has been studied in both mild to moderate hypertensive patients (sitting diastolic blood
pressure between 95 and 115 mmHg) and severe hypertensive patients (sitting diastolic blood
pressure between 115 and 125 mmHg).
Eprosartan’s effect on mortality and cardiovascular morbidity is not currently known.
In normal adult males, eprosartan has been shown to increase mean effective renal plasma flow.
Eprosartan does not reduce glomerular filtration rate in healthy males, in hypertensive patients
or in patients with varying degrees of renal insufficiency. Eprosartan has a natriuretic effect on
normal subjects on a low-salt diet.
Eprosartan has no significant effect on the excretion of uric acid.

Eprosartan does not potentiate the effects of (ACE-mediated) bradykinin, e.g. cough.
In a study specifically aimed at comparing the incidence of cough in patients treated with
eprosartan or an ACE inhibitor, the incidence of a persistent dry cough was significantly lower
(p<0,05) in the patients treated with eprosartan (1.5%) than in patients treated with an ACE
inhibitor (5.4%). In another study of the incidence of cough in patients who had earlier coughed
whilst taking an ACE inhibitor, the incidence of persistent dry cough was 2.6% in the
eprosartan group, 2.7% in the placebo group and 25.0% in the group treated with an ACE
inhibitor. The difference in the incidence of persistent dry cough between the eprosartan group
and the ACE inhibitor group was statistically significant (p<0.01), whereas the difference
between the eprosartan group and the placebo group was not.

It emerged from three clinical studies (n=791) that the blood pressure-lowering effect of
eprosartan was at least as high as that of an ACE inhibitor.

In two big randomised controlled trials (ONTARGET – ONgoing Telmisartan Alone and in
combination with Ramipril Global Endpoint Trial and VA NEPHRON-D – The Veterans
Affairs Nephropathy in Diabetes) the use of the combination of an ACE inhibitor with an
angiotensin II receptor antagonist was investigated.

ONTARGET was a study in patients with a history of cardiovascular or cerebrovascular
disease, or type 2 diabetes mellitus in combination with signs of target organ damage. VA
NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. In
these studies no relevant positive effect on renal function and/or cardiovascular outcomes and
mortality was found, while an increased risk of hyperkalaemia, acute renal damage and/or
hypotension was seen compared with monotherapy. In view of their corresponding
pharmacodynamic properties these outcomes are also relevant for other ACE inhibitors and
angiotensin II receptor antagonists.
ACE inhibitors and angiotensin II receptor antagonists should therefore not be taken
concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease
Endpoints) was a study that was set up to investigate the advantage of adding aliskiren to the
standard treatment of an ACE inhibitor or an angiotensin II receptor antagonist in patients with
type 2 diabetes mellitus and chronic renal disease, cardiovascular disease or both. The study
was terminated prematurely because of an increased risk of negative outcomes.
Cardiovascular mortality and stroke both occurred numerically more frequently in the aliskiren
group than in the placebo group, while undesirable effects and major severe undesirable effects
(hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the
aliskiren group than in the placebo group.

Absolute bioavailability after a single 300-mg oral dose of eprosartan is approximately 13%,
due to limited oral absorption. The peak concentration of eprosartan (when fasting) is reached
after 1-2 hours. Between 100 and 200 mg, the plasma concentration is directly doseproportional,
but at doses of 400 and 800 mg this is less the case. The terminal elimination halflife
of eprosartan after oral administration is 5 to 9 hours.
Chronic use of eprosartan does not show any significant accumulation. Administration of
eprosartan with food delays absorption, with minor changes observed (< 25%) in Cmax and
AUC, which are not, however, of clinical significance.

Plasma protein binding of eprosartan is high (approximately 98%) and constant in the whole
concentration range of the therapeutic doses. The extent of protein-binding is not influenced by
gender, age, hepatic dysfunction or a mild to moderate/severe renal impairment, but in a small
number of patients with severe renal impairment it is seen to decrease.
Eprosartan can be administered in combination with lipid-lowering drugs, such as lovastatin,
simvastatin, pravastatin, fenofibrate, gemfibrizole and niacin.
Following intravenous administration of [14C] eprosartan, about 61% of radioactivity is
recovered in the faeces and about 37% in the urine. Following oral administration of [14C]
eprosartan, about 90% of radioactivity is recovered in the faeces and about 7% in the urine.

Following oral and intravenous administration of [14C] eprosartan to human subjects, only
eprosartan is recovered in the plasma and the faeces. In the urine, approximately 20% of the radioactivity excreted consisted of an acyl glucuronide of eprosartan, whilst the remaining 80%
consisted of unchanged eprosartan.
The volume of distribution of eprosartan is about 13 litres. Total plasma clearance is about 130
ml/min. Biliary and renal excretion contribute to the elimination of eprosartan.
Both AUC and Cmax values of eprosartan are higher in elderly patients (on average,
approximately twice as high), but the dose does not have to be adjusted on this basis.
In patients with impaired renal function, the AUC values (but not the Cmax values) of eprosartan
(single 100 mg dose) are on average approximately 40% higher.
Compared with subjects with normal renal function, the mean AUC and Cmax values in patients
with moderately impaired renal function (creatinine clearance 30-59 ml/min) are approximately
30% higher, and in patients with severely impaired renal function (creatinine clearance 5-29
ml/min) are approximately 50% higher and in dialysis patients approximately 60% higher.
There are no differences in the pharmacokinetics of eprosartan between males and females.

General toxicology
Oral doses of eprosartan up to 1,000 mg/kg/daily for a maximum of 6 months in rats and for a
maximum of 1 year in dogs caused no significant drug-related toxicity at all.
Reproductive and developmental toxicity
In pregnant rabbits, eprosartan at 10 mg/kg/daily showed maternal and foetal toxicity only
during the last part of pregnancy. At 3 mg/kg/daily, maternal toxicity was observed, but no
foetal toxicity.
Genotoxicity
In a series of in vitro and in vivo studies, no genotoxicity was observed.
Carcinogenicity
In rats and mice that were given up to 600 and 2,000 mg/kg/daily respectively for 2 years, no
carcinogenicity was observed.

Tablet core
600 mg tablet:
lactose monohydrate, microcrystalline cellulose, pregelatinised starch, crospovidone
magnesium stearate and purified water
Tablet coating
600 mg tablet:
Hypromellose (E464), macrogol 400, polysorbate 80 (E433), titanium dioxide (E171).

Not applicable.

Teveten 600: 3 years.

Do not store above 25 °C.
Store in the original container.

Teveten 600:
White PVC/PVDC/Al blister: 14, 28 or 56 tablets in a blister pack.
White PVC/PCTFE/Al blister: 14, 28 or 56tablets in a blister pack.

Not applicable.