Essential hypertension.

The recommended dose is 600 mg once daily.

In most patients, the maximum blood pressure-lowering effect is achieved 2 to 3 weeks after initiation of therapy.

Eprosartan may be used as monotherapy or in combination with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1). In particular, thiazide diuretics such as hydrochlorothiazide or calcium channel blockers have been shown to have an additive effect on eprosartan.

Eprosartan can be taken with or without food.

Geriatric patients

No dose adjustment is required in the elderly.

Dosage in hepatically impaired patients

Dose adjustment is not required in patients with mildly to moderately impaired hepatic function.

Eprosartan is contraindicated in patients with severely impaired hepatic function (see section 4.3).

Dosage in renally impaired patients

In patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min), the daily dose should not exceed 600 mg.

Paediatric patients

Teveten is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

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

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

 

Hepatic impairment

When eprosartan is used in patients with mild to moderate hepatic impairment, special care should be exercised due to the fact that there is limited experience in this patient population.

Renal impairment

In patients with moderate to severe impaired renal function (creatinine clearance < 60 ml/min), the daily dose should not exceed 600 mg. Caution should be exercised when used by patients with a creatinine clearance < 30 ml/min and when used by patients undergoing dialysis. Eprosartan is contraindicated in patients with severe unilateral or bilateral renal artery stenosis (see section 4.3). In patients with impaired renal function, e.g., due to renal artery stenosis, the possibility of acute deterioration of renal function should be considered. In such patients, monitoring of renal function during treatment is recommended.

Caution should be exercised in patients undergoing haemodialysis. There is no available experience with the administration of eprosartan in patients who have recently undergone renal transplantation.

Patients at risk of impaired renal function

Some patients whose renal function depends on the continued inherent activity of the reninangiotensin-aldosterone system (e.g., patients with severe cardiac insufficiency [NYHA classification: class IV], bilateral renal artery stenosis or renal artery stenosis of a solitary kidney) are at risk of developing oliguria and/or progressive azotaemia and, in rare cases, acute renal dysfunction during treatment with an angiotensin-converting enzyme (ACE) inhibitor. Patients treated concomitantly with a diuretic are more likely to develop these symptoms. In patients susceptible to this, there is insufficient therapeutic experience with angiotensin II receptor blockers, such as eprosartan, to determine whether there is a similar risk of compromising renal function. When eprosartan is used in patients with impaired renal function, renal function should be assessed before starting treatment with eprosartan and also at intervals during therapy. If deterioration of renal function is observed during therapy, treatment with eprosartan should be reassessed.

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

Hyperkalaemia

Hyperkalaemia may occur during treatment with other drugs that act on the renin-angiotensinaldosterone system. This is particularly true in patients with renal impairment and/or heart failure. In patients at risk, close monitoring of serum potassium is recommended.

Based on experience with the use of other medicinal products that act on the renin-angiotensinaldosterone system, the concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other agents that may increase serum potassium (e.g., heparin, drugs containing trimethoprim) may lead to increases in serum potassium. Coadministration of these agents with eprosartan should therefore be done cautiously.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and impaired renal function (including acute renal failure). 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 double blockade is considered absolutely necessary, this should only be done under the supervision of a specialist and renal function, electrolytes and blood pressure should be monitored regularly.

ACE inhibitors and angiotensin II receptor antagonists should not be taken concomitantly 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 (such as when administering high doses of diuretics), symptomatic hypotension may occur after starting eprosartan therapy. Sodium and/or volume depletion should be corrected before starting with eprosartan treatment, or the set dose of diuretics should be reduced.

Coronary heart disease

There is limited experience in patients with coronary artery disease.

Aortic and mitral valve stenosis and hypertrophic cardiomyopathy

As with 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 planning pregnancy should be converted to an alternative antihypertensive therapy with a known safety profile for use during pregnancy, unless continued treatment with angiotensin II receptor antagonists is deemed necessary. If pregnancy is identified, angiotensin II receptor antagonist treatment should be discontinued immediately and, if necessary, started on alternative therapy (see sections 4.3 and 4.6).

Other warnings and precautions

As observed for angiotensin-converting enzyme inhibitors, eprosartan and the other angiotensin II receptor antagonists are apparently less effective at lowering blood pressure in black people than in non-black people, possibly because of a higher prevalence of low renin in the black hypertensive population.

Lactose

Patients with rare hereditary conditions 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 during the first trimester of pregnancy is not recommended (see section 4.4). Angiotensin II receptor antagonist use is contraindicated during the second and third trimesters of pregnancy (see section 4.3 and 4.4).

No clear conclusions can be drawn from results of epidemiological studies on the risk of teratogenic effects due to exposure to angiotensin-2-receptor antagonists during the first trimester of pregnancy; however, a small increase in risk cannot be ruled out. While there is no controlled epidemiological data on the risk with angiotensin-2-receptor antagonists, the risk may be similar with this class of drugs. Patients planning pregnancy should be switched to another antihypertensive therapy with a known safety profile for use during pregnancy unless continued treatment with an angiotensin II receptor antagonist is deemed necessary. If pregnancy is established, angiotensin II receptor antagonist treatment should be discontinued immediately, and alternative therapy should be started if necessary.

It is known that exposure to angiotensin II receptor antagonists during the second and third trimester can induce foetal toxicity (worsened renal function, oligohydramnios, delayed skull hardening) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3). Where exposure to angiotensin II receptor antagonists has occurred from the second trimester of pregnancy, ultrasound scanning of renal function and skull is recommended. New-borns whose mothers have used angiotensin II receptor antagonists should be closely monitored for hypotension (see also section 4.3 and 4.4).

Lactation

As no information is available on the use of Teveten during breast-feeding, Teveten is not recommended and alternative treatments with a known safety profile for use during breast-feeding are preferred, especially when feeding neonates or preterm infants.

The effect of eprosartan on the ability to drive and operate machinery has not been studied, however, based on pharmacological properties, an effect is unlikely. When driving and operating machinery, however, it should be taken into account that dizziness or fatigue may sometimes occur with the treatment of hypertension. 

The most commonly reported adverse reactions in patients treated with eprosartan are headache and non-specific gastrointestinal symptoms, which occur in about 11 and 8% of patients, respectively.

The following adverse reactions have been reported in clinical trials in which patients were treated with eprosartan (n = 2316).

Side effects are listed by system/organ class with what 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,shortness of breath, Pharyngitis, Dyspnoea, Upper respiratory tract infection, Cough, Sinusitis, Bronchitis
Gastrointestinal disorders		Non-specific gastrointestinal system disorders (e.g. nausea, diarrhoea, vomiting), Abdominal pain, Dyspepsia
Liver and bile disorders					Abnormalities in hepatic function
Skin and subcutaneous tissue disorders		Allergic skin reactions (e.g. rash, pruritus)	Angiooedema*			Facial swelling
Musculoskeletal and connective tissue disorders		Arthralgia, Myalgia, Back pain
Kidney and urinary track  disorders		Urinary tract infection				Reduced renal function including renal failure in highrisk patients (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 with higher frequency than in placebo.

The following adverse reactions have been reported spontaneously during post marketing use of eprosartan, in addition to those reported during clinical trials. Frequencies cannot be determined from the available data (not known).

Renal and urinary disorders

Impaired renal function including renal failure in patients at risk (e.g., renal artery stenosis).

For azilsartan, eprosartan and telmisartan:

Description of selected adverse reactions:

Cases of intestinal angioedema have been reported after the use of angiotensin II receptor antagonists (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

To report any side effect(s):
-National Pharmacovigilance Center (NPC)

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 have been individual reports of doses of up to 12,000 mg ingested post-market. Most patients have reported no symptoms. One individual experienced a circulatory collapse after ingesting 12,000 mg of eprosartan. This individual made a full recovery. The most likely manifestation of overdose is hypotension. The patient should then be placed in a lying position, after which saline and fluids can be administered. Treatment should be symptomatic and supportive. Depending on the time elapsed since ingestion, treatment may include inducing vomiting, gastric lavage and/or administration of activated charcoal.

Eprosartan cannot be removed by 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 selectively binds 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., vascular smooth muscle, adrenals, kidneys and heart) and triggers several important biological mechanisms, such as vasoconstriction, sodium retention and aldosterone release.

In healthy volunteers, eprosartan antagonises the effect of angiotensin II on blood pressure, renal blood flow and aldosterone secretion. Whether eprosartan is administered in a single dose or two half-doses, it has a similar effect on blood pressure in patients with hypertension. This effect on blood pressure is maintained evenly over a 24-hour period. In patients with hypertension, reduction in blood pressure caused no change in 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 with nitrendipine. In the eprosartan group, 78% of 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 an openlabel randomised prospective design, blinded to observers. The primary composite endpoint included all-cause mortality, cerebrovascular events (TIA, PRIND, stroke) and cardiovascular events (unstable angina, myocardial infarction, heart failure, pulmonary embolism and fatal cardiac arrhythmia) including recurrent events. In both treatment arms, blood pressure targets were achieved and maintained over the course of the study. The primary endpoint showed a significantly better outcome in the eprosartan group (risk reduction by 21%). The numerical risk reduction in the first event analysis was 12% for the cerebrovascular and 30% for the cardiovascular endpoints. These results were mainly driven by 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 681 patients died versus 52 of 671 patients in the nitrendipine group (HR 1.07, 95% BI 0.73 -1.56, p=0.725). Fatal and non-fatal myocardial infarction occurred in 18 versus 20 and stroke in 36 versus 42 patients, numerically in favour of eprosartan. For the primary endpoint, the effect of eprosartan appeared to be more pronounced in patients who did not receive beta-blockers.

In hypertensive patients, eprosartan does not affect fasting triglyceride, total cholesterol or LDL cholesterol levels. In addition, eprosartan has no effect on fasting blood sugar levels.

Eprosartan has been studied in patients with both mildly to moderately elevated blood pressure (diastolic blood pressure, measured sitting, between 95- and 115-mm Hg) and severely elevated blood pressure (diastolic blood pressure measured sitting, between 115- and 125-mm Hg).

The impact of eprosartan on mortality and cardiovascular morbidity are currently unknown.

Eprosartan has been shown to increase mean effective renal plasma flow in normal adult males. 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 in normal subjects following a low-salt diet.

Eprosartan does not significantly affect uric acid excretion.

Eprosartan does not potentiate the effects associated with bradykinin (due to ACE), e.g., cough. In a study specifically aimed at comparing the incidence of cough in patients treated with either eprosartan or an ACE inhibitor, the incidence of persistent dry cough was found to be significantly lower (p<0.05) in eprosartan-treated patients (1.5%) than in patients treated with an ACE inhibitor (5.4%). From another study of the incidence of cough in patients who had previously coughed while 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 ACE inhibitor-treated group. The difference in incidence of persistent dry cough between the eprosartan group and the ACE inhibitor group was statistically significant (p<0.01), while the difference between the eprosartan group and the placebo group was not.

Three clinical studies (n=791) showed that the blood pressure-lowering effect of eprosartan was at least equal to that of an ACE inhibitor.

Two large, 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) investigated the use of the combination of an ACE inhibitor with an angiotensin II receptor antagonist.

ONTARGET was a study in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus combined with signs of end-organ damage. VA NEPHROND was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies found no relevant positive effect on renal function and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension was seen compared with monotherapy. Given 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 designed to investigate the benefit 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 kidney disease, cardiovascular disease or both. The study was terminated early due to an increased risk of adverse outcomes.

Cardiovascular mortality and stroke were both numerically more common in the aliskiren group than in the placebo group, while adverse events and major serious adverse events (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

The absolute bioavailability after a single 300-mg oral dose of eprosartan is about 13%, due to limited oral absorption. The peak concentration of eprosartan (fasting stomach) is reached after 1-2 hours. Plasma concentrations are dose proportional from 100 to 200 mg, but less so at doses of 400 and 800 mg. The terminal elimination half-life of eprosartan after oral administration is 5 to 9 hours.

Eprosartan does not significantly accumulate with chronic use. Administration of eprosartan with food delays absorption with minor changes (< 25%) observed in Cmax and AUC, which, however, are not of clinical significance.

Plasma protein binding of eprosartan is high (about 98%) and constant across the concentration range of therapeutic doses. The extent of plasma protein binding is not affected by gender, age, hepatic impairment or mild to moderate/serious renal impairment, but it was shown to be decreased in a small number of patients with severe renal impairment.

Eprosartan can be administered in combination with lipid-lowering drugs, such as lovastatin, simvastatin, pravastatin, fenofibrate, gemfibrozil and niacin.

Following intravenous administration of [14C] eprosartan, about 61% of radioactivity is recovered in faeces and about 37% in urine. Following oral administration of [14C] eprosartan, approximately 90% of the radioactivity is recovered in the faeces and approximately 7% in the urine.

Following oral and intravenous administration of [14C] eprosartan to human subjects, exclusively eprosartan was recovered in plasma and faeces. About 20% of the radioactivity excreted in urine consisted of an acyl glucuronide of eprosartan, while the remaining 80% consisted of unchanged eprosartan.

The volume of distribution of eprosartan is about 13 litres. The total plasma clearance is about 130 ml/min. Biliary and renal excretion contribute to the elimination of eprosartan.

Both the AUC and Cmax values of eprosartan are higher in elderly patients (on average approximately twice as high), but this does not necessitate alterations in dosing.

In patients with impaired liver function, the AUC values (but not Cmax values) of eprosartan (single dose of 100 mg) were on average about 40% higher.

Compared to subjects with normal renal function, mean AUC and Cmax values were about 30% higher in patients with moderately renal impairment (creatinine clearance 30-59 ml/min), about 50% higher in patients with severely renal impairment (creatinine clearance 5-29 ml/min) and about 60% higher in dialysis patients.

There is no difference in the pharmacokinetics of eprosartan between males and females.

General toxicology

Oral doses of eprosartan up to 1,000 mg/kg/day for up to 6 months in rats and for up to 1 year in dogs did not cause any significant drug-related toxicity.

Reproductive and developmental toxicity

In pregnant rabbits, eprosartan at 10 mg/kg/day only exhibited maternal and foetal toxicity during the latter part of pregnancy. At 3 mg/kg/day, maternal but not foetal toxicity was observed.

Genotoxicity

Genotoxicity was not observed in a battery of in vitro and in vivo tests.

Carcinogenicity

No carcinogenicity was observed in rats and mice given up to 600 or 2,000 mg/kg/day for 2 years, respectively.

Tablet core
600 mg tablet:
lactose monohydrate, microcrystalline cellulose, pregelatinized maize starch, crospovidone and magnesium stearate
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 or 28 tablets in a blister pack.

White PVC/PCTFE/Al-blisters: 14 or 28 tablets in a blister pack.

Not applicable.