EUPRESSYL LP 60 mg Prolonged-release capsule Bottle/30

Prolonged-release capsule (with a light blue transparent body and an opaque white cap).
Bottle of 30, with desiccant (silica gel). Box of 1.

For a prolonged-release capsule:

Urapidil: 60,000 mg

Excipient(s) with known effect: sucrose

Excipients:

Arterial hypertension.

Dosage :

In adults in monotherapy, the recommended dose is 120 mg per day in 2 doses. This dose should be adjusted to the therapeutic response without however exceeding 180 mg per day in 2 doses.

In some patients, a dose of 60 mg per day in 2 doses is sufficient.

Special populations :

In elderly subjects in monotherapy, the recommended dose is 60 mg per day in 2 doses (the 30 mg strength is better suited); in case of inefficacy it may be increased to 120 mg per day in 2 doses.

In patients with moderate to severe renal impairment, a dose reduction may be considered in the case of long-term treatment.

In patients with severe hepatic impairment, a dose reduction may be considered.

Method of administration :

Prolonged-release capsules must be taken during the morning and evening meals, and must be swallowed with a little liquid.

No exaggerated first-dose effect has been demonstrated and there has been no rebound effect upon abrupt discontinuation of treatment.

It is not necessary to modify the dose in long-term treatments due to the absence of tachyphylaxis.

Association with other antihypertensive medicinal products is possible, in particular diuretics and beta-blockers.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

• Particular monitoring should be carried out in patients with heart failure of mechanical origin, i.e. aortic or mitral stenosis, pulmonary embolism, or disturbance of cardiac function linked to pericardial disease.
• In patients who are hypovolaemic (diarrhoea, vomiting) and/or sodium-depleted, initial doses will be low, then adjusted according to clinical and biological progression (risk of increased antihypertensive action of urapidil).
• In elderly subjects (see section Dosage and administration).
• In patients with moderate to severe renal impairment (see section Dosage and administration).
• In case of severe impairment of hepatic function, it is recommended to reduce doses, particularly for long-term treatment.
• In cases of general anaesthesia for major surgery or when anaesthesia is given with potentially hypotensive agents, urapidil may cause a certain degree of hypotension which will need to be corrected by volume expansion.
• Patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase/isomaltase deficiency (rare hereditary diseases) must not take this medicine.

Paediatric population :

In the absence of available data, do not use in children.

Combinations not recommended

+ Urological alpha-blockers

Potentiation of the hypotensive effect. Risk of severe orthostatic hypotension.

Associations requiring precautions for use

+ Baclofen : Increased risk of hypotension, particularly orthostatic. Monitor blood pressure and adjust the antihypertensive dose if necessary.

+ Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil): Risk of orthostatic hypotension, particularly in elderly subjects. Start treatment at the recommended minimum doses and gradually adjust doses if needed.

Associations to be taken into account

+ Amifostine : Increased hypotension, particularly orthostatic.

+ Tricyclic antidepressants : Increased risk of hypotension, particularly orthostatic.

+ Neuroleptics : Increased risk of hypotension, particularly orthostatic.

+ Antihypertensives except alpha-blockers : Increased hypotensive effect. Increased risk of orthostatic hypotension.

+ Nitrates and related compounds: Increased risk of hypotension, particularly orthostatic hypotension.

+ Glucocorticoids (except hydrocortisone for substitution therapy) and mineralocorticoids: Decreased antihypertensive effect (sodium and water retention by corticosteroids).

Pregnancy

There are no data or limited data on the use of urapidil in pregnant women.

Studies performed in animals have demonstrated reproductive toxicity (see section Preclinical safety).

Urapidil is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

In the absence of data on passage into breast milk, breastfeeding is not recommended during treatment with urapidil.

Fertility

Animal studies have shown a decrease in fertility (see section Preclinical safety).

Response to treatment may vary from one patient to another. Urapidil may impair the ability to drive vehicles or operate machinery, particularly at the beginning of treatment, when treatment is changed, and when alcohol is taken concomitantly.

Cardiovascular disorders:

• uncommon: palpitations, tachycardia;
• very rare: orthostatic hypotension.

Gastrointestinal disorders:

• common: nausea;
• rare: epigastric pain, dry mouth, vomiting, diarrhoea.

Skin disorders:

• very rare: hypersensitivity such as pruritus, erythema and skin rash;
• frequency not known: angioedema, urticaria.

Changes in biological parameters:

• very rare: reversible elevation of liver enzymes, thrombocytopenia.

General disorders and administration site conditions:

• rare: asthenia.

Central nervous system disorders:

• common: dizziness, headache.

Psychiatric disorders:

• rare: sleep disorders, agitation.

Genitourinary disorders:

• very rare: worsening of urinary incontinence, urinary urgency, ejaculation disorder, impotence or priapism.

Respiratory, thoracic and mediastinal disorders:

• nasal congestion.

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 the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.

Symptoms:

The clinical manifestations are of circulatory and neurological type:

• circulatory system: dizziness, orthostatic hypotension, collapse;
• central nervous system: fatigue, decreased reaction speed.

Action to be taken:        

Lay the patient down and institute standard treatment for arterial hypotension (fluid replacement, catecholamines if necessary).

Pharmacotherapeutic class: Antihypertensive, peripherally acting adrenolytic/Alpha blocker, ATC code: C02CA06.

Vasodilator acting through blockade of post-synaptic peripheral alpha-1-adrenergic receptors and through an effect on central regulation of blood pressure and sympathetic tone by inhibition of alpha-1-adrenergic receptors and stimulation of 5-HT_1A serotonergic receptors. In hypertensive patients, these effects rapidly result in a decrease in systolic and diastolic blood pressures, supine, standing, at rest and during exertion, without reflex increase in heart rate.

The decrease in blood pressure is secondary to a reduction in total peripheral resistance (for example at the renal level, where blood flow increases) without change in cardiac output.

When pulmonary resistance is increased, for the same dose of urapidil, the reduction in these resistances is greater than that of total peripheral resistance.

No potentiation of bronchospasm has been observed. Renin and aldosterone secretion are not increased. No first-dose effect, tachyphylaxis or rebound phenomenon has been observed.

In studies, urapidil did not modify hydroelectrolytic balance, lipid metabolism, carbohydrate tolerance, hepatic and renal functions and/or haematological parameters.

Urapidil has no deleterious effect on lipid parameters, and certain studies showed in hypertensive and hypercholesterolaemic patients a tendency toward a lowering of blood total cholesterol and triglyceride levels. The clinical significance of these changes is not established.

In patients suffering from lung disease with chronic respiratory insufficiency (hypoxia and hypercapnia) and secondary pulmonary arterial hypertension, several studies have shown that urapidil had a vasodilatory action on the pulmonary circulation; there is no harmful effect on ventilatory function, bronchoreactivity and gas exchange.

After oral administration, the maximum serum concentration is reached after 4-6 h. Absolute bioavailability is 72 %. The mean serum elimination half-life is 4,7 h.

Urapidil is metabolised essentially in the liver into three metabolites, the main one in humans being the parahydroxylated derivative (M1), which is inactive.

30 to 50 % of the administered dose is eliminated as metabolites in the urine, as well as 10 to 15 % of the unchanged parent product. The remainder is eliminated in the faeces.

Plasma protein binding is 80 %.

Renal impairment : in patients with advanced renal insufficiency, clearance is reduced and plasma half-life is longer.

Hepatic impairment : in patients with advanced hepatic insufficiency, clearance is reduced and plasma half-life is longer

Lengthening of the oestrous cycle has been observed in rats and mice, but the relevance for humans is not known. Although there was no impact on fertility in mice, a decrease in fertility has been reported in rats. Embryo-foetal developmental toxicity studies showed an embryo-lethal effect, but no teratogenic effect in mice, rats and rabbits. In a pre- and post-natal developmental toxicity study, a decrease in perinatal survival and body weight was observed in the pups of the F1 generation.

18 months

No special precautions for storage.

No particular requirements

List I

Marketing authorisation (AMM)

CIP 3400936093225 (Fl/30).

Price:

6,90 euros (Fl/30).

Social security reimbursement at 65%. Collective.

 

Marketing authorisation holder: Cheplapharm Arzneimittel GmbH, Ziegelhof 24, 17489 Greifswald, Germany.