4.1. Therapeutic indications

Eprosartan is indicated for the treatment of essential hypertension.

4.2. Posology and method of administration

Posology

The recommended dose is 600 mg eprosartan once daily.

Achievement of maximal blood pressure reduction in most patients may take 2 to 3 weeks of treatment.

Eprosartan may be used alone or in combination with other anti-hypertensives (see sections 4.3, 4.4, 4.5 and 5.1). In particular, addition of a thiazide-type diuretic such as hydrochlorothiazide or a calcium channel blocker such as sustained release nifedipine has been shown to have an additive effect with eprosartan.

Eprosartan may be taken with or without food.

Geriatric patients

No dose adjustment is required in the elderly.

Dosage in hepatically impaired patients: There is limited experience in patients with hepatic insufficiency (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 600mg.

Paediatric population: Eprosartan is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed 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 of a solitary functioning kidney

The concomitant use of Eprosartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4. Special warnings and precautions for use

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, Eprosartan 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

No dose adjustment is required in patients with mild to moderate renal insufficiency (creatinine clearance ≥ 30 ml/min). Caution is recommended for use in patients with creatinine clearance < 30 ml/min or in patients undergoing dialysis.

Patients at risk of renal impairment

Some patients whose renal function is dependent on the continued inherent activity of the renin-angiotensin-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) have risks of developing oliguria and/or progressive azotaemia and rarely acute renal failure during therapy with an angiotensin converting enzyme (ACE) inhibitor. These events are more likely to occur in patients treated concomitantly with a diuretic. Angiotensin II receptor blockers such as eprosartan have not had adequate therapeutic experience to determine if there is a similar risk of developing renal function compromise in these susceptible patients. When eprosartan is to be used in patients with renal impairment, renal function should be assessed before starting treatment with eprosartan and at intervals during the course of therapy. If worsening of renal function is observed during therapy, treatment with eprosartan should be reassessed.

The following precautions have been included based on experience with other agents in this class and also ACE inhibitors:

Hypotension

Symptomatic hypotension may occur in patients with severe sodium depletion and/or volume depletion (e.g. high dose diuretic therapy). These conditions should be corrected before commencing therapy.

Coronary heart disease

There is limited experience in patients with coronary heart disease.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy.

As with other vasodilators, eprosartan should be used with caution in patients with aortic and mitral valve stenosis or hypertrophic cardiomyopathy.

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

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are not recommended to be treated with eprosartan.

Renal transplantation

There is no experience in patients with recent kidney transplantation.

Hyperkalaemia

During treatment with other medicinal products which affect the renin­angiotensin­aldosterone system hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Adequate monitoring of serum potassium in patients at risk is recommended.

Based on experience with the use of other medicinal products which affect the renin­angiotensinaldosterone system, concomitant use of potassium­sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products which may increase the potassium level (e.g. heparin, trimethoprim containing medicines) may lead to an increase in serum potassium and should therefore be co­administered cautiously with Eprosartan.

Pregnancy

Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continued angiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers 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, eprosartan and the other angiotensin II receptor blockers are apparently less effective in lowering blood pressure in black people than in non­blacks, possibly because of higher prevalence of low­renin states in the black hypertensive population.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Since in placebo­controlled clinical studies significantly elevated serum potassium concentration were observed, and based on experience with the use of other drugs that affect the renin­angiotensinaldosterone system, concomitant use of K­sparing diuretics, K­supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin, trimethoprim containing medicines) may lead to increase in serum potassium.

Clinical trial data has shown that dual blockade of the renin­angiotensin­aldosterone­system (RAAS) through the combined use of ACE­inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS acting agent (see sections 4.3, 4.4 and 5.1).

The antihypertensive effect may be potentiated by other antihypertensives

Toxicity and a reversible increase in serum lithium concentrations have been reported during concomitant administration of lithium with ACE inhibitors.The possibility of a similar effect cannot be excluded and careful monitoring of serum lithium levels is recommended during concomitant use.

Eprosartan has been shown not to inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E and 3A in vitro.

As with ACE inhibitors, concomitant use of angiotensin II receptor blockers 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.

Concomitant use of losartan with the NSAID indometacin led to a decrease in efficacy of the angiotensin II receptor blocker; a class effect cannot be excluded.

4.6. Fertility, pregnancy and lactation

Pregnancy

The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor blockers is contraindicated during second and third trimester 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 blockers, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor blockers therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor blockers therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to angiotensin II receptor blockers have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor blockers should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of Eprosartan during breast-feeding, Eprosartan 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

The effect of eprosartan on the ability to drive and use machines has not been studied, but based on its pharmacodynamic properties, eprosartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account, that occasionally dizziness or weariness may occur during treatment of hypertension.

4.8. Undesirable effects

Clinical Trials

The most commonly reported adverse drug reactions of patients treated with eprosartan are headache and unspecific gastrointestinal complaints, occurring in approximately 11% and 8%, respectively, of patients.

ADVERSE EVENTS REPORTED DURING CLINICAL TRIALS IN PATIENTS TREATED WITH EPROSARTAN (n = 2316)

MedDRA system organ class

Very common

≥ 1/10

Common

≥ 1/100 to 1</10

Uncommon

≥ 1/1,000 to <1/100

Immune system disorders

Hypersensitivity*

Nervous system disorders

Headache*

Dizziness*

Vascular disorders

Hypotension

Respiratory, thoracic and mediastinal disorders

Rhinitis

Gastrointestinal disorders

Unspecific gastrointestinal complaints (e.g., nausea, diarrhoea, vomiting)

Skin and subcutaneous tissue disorders

Allergic skin reactions (e.g. rash, pruritus)

Angioedema*

General disorders and administration site reactions

Asthenia

(*) Did not occur in a higher frequency than in placebo

Postmarketing experience

In addition to those adverse events reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of eprosartan. A frequency cannot be estimated from the available data (not known).

Gastrointestinal disorders

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

Renal and urinary disorders

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

Muskuloskeletal and connective tissue disorder

Arthralgia

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Limited data are available with regard to overdosage in humans. Eprosartan was well tolerated after oral dosing with no mortality in rats and mice up to 3000 mg/kg and in dogs up to 1000 mg/kg.

In humans, there have been individual reports from postmarketing experience where doses up to 12,000 mg had been ingested. Most patients reported no symptoms. In one subject circulatory collapse occurred after ingestion of 12,000 mg eprosartan. The subject recovered completely.

The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension occurs, supportive treatment should be instituted.