Xatral
summary of product characteristics
1Name of the Medicinal Product
Xatral 2.5 mg film-coated tablets
Xatral 5 mg prolonged-release tablets
2Qualitative and Quantitative Composition
Film coated tablets: Alfuzosin hydrochloride 2.5 mg
Prolonged-release tablets: Alfuzosin hydrochloride 5 mg
Excipients with known effects:
Xatral 2.5 mg film-coated tablets: lactose 61 mg
Xatral 5 mg prolonged-release tablets: hydrogenated castor oil 19.6 mg
For the full list of excipients, see section 6.1.
3Pharmaceutical Form
Film-coated tablet
Prolonged-release tablet
Film-coated tablet 2.5 mg: white round film-coated.
Prolonged-release tablet 5 mg: yellow, round, biconvex, film-coated.
4Clinical Particulars
.4.1Therapeutic indications
Treatment of moderate to severe symptoms of benign prostatic hyperplasia.
.4.2Posology and method of administration
Adults:1 prolonged-release tablet5 mg morning and evening. The prolonged-release tablet should be swallowed whole. The first dose should be taken at bedtime.
Older people:1 prolonged-release tablet5 mg daily. The first dose should be taken at bedtime. The dose may be increased to 10 mg daily, given as 1 prolonged-release tablet 5 mg twice daily.
In reduced renal function: 1 prolonged-release tablet5 mg daily. The first dose should be taken at bedtime. The dose is to be adjusted according to clinical response.
In mild to moderate liver insufficiency:1 tablet2.5 mg daily. The dose may be increased to 1 tablet 2.5 mgtwice daily, depending on clinical response.
Paediatric population:
Efficacy of alfuzosin has not been demonstrated in children aged 2 to 16 years (see section 5.1). Therefore, alfuzosin is not indicated for use in paediatric population.
.4.3Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Conditions with orthostatic hypotension.
Severe liver insufficiency.
Combination with other alpha-1-blockers.
.4.4Special warnings and precautions for use
Xatral should be given with caution to patients who are on antihypertensive medication or nitrates.
In some subjects postural hypotension may develop, with or without symptom (dizziness, fatigue, sweating) within a few hours following administration. These effects are transient, occur in the beginning of treatment and do not usually prevent the continuation of treatment.
Pronounced drop in blood pressure has been reported in post-marketing surveillance in patients with pre‑existing risk factors (such as underlying cardiac diseases and/or concomitant treatment with anti‑hypertensive medication). The risk of developing hypotension and related adverse reactions may be greater in older people.
There is a risk of cerebral ischemic disorders in patients with symptomatic or asymptomatic pre-existing cerebral circulatory disturbances, due to the fact that hypotension may develop following alfuzosin administration (see section 4.8).
Care should be taken when alfuzosin is administered to patients who have had a pronounced hypotensive response to another alpha-1-blocker.
In coronary patients, the specific treatment for coronary insufficiency should be continued. If angina pectoris reappears or worsens, alfuzosin should be discontinued.
As with all alpha-1-blockers, alfuzosin should be used with caution in patients with acute cardiac failure.
Patients with congenital QTc prolongation, with a known history of acquired QTc prolongation or who are taking drugs known to increase the QTc interval should be evaluated before and during the administration of alfuzosin.
The “Intraoperative Floppy Iris Syndrome” (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. Isolated reports have also been received with other alpha‑1‑blockers and the possibility of a class effect cannot be excluded. As IFIS may lead to increased procedural complications during the cataract operation current or past use of alpha‑1‑blockers should be made known to the ophthalmic surgeon in advance of surgery.
Xatral 2.5 mg film-coated tablets:
Xatral 2.5 mg film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose‑galactose malabsorption should not take this medicine.
Xatral 5 mg prolonged-release tablets:
The excipient hydrogenated castor oil may cause stomach upset and diarrhoea.
.4.5Interaction with other medicinal products and other forms of interaction
No pharmacodynamic or pharmacokinetic interactions have been observed in studies with healthy volunteers between alfuzosin and the following drugs: warfarin, digoxin, hydrochlorothiazide and atenolol.
Administration of general anaesthetics to a patient treated with alfuzosin may lead to blood pressure instability.
Combinations contra-indicated:
Alpha-1-receptor blockers (see section 4.3)
Combinations to be taken into account:
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Antihypertensive drugs (see section 4.4)
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Nitrates (see section 4.4)
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Potent CYP3A4 inhibitors such as itraconazole, ketoconazole, protease inhibitors, clarithromycin, telithromycin and nefazodone since alfuzosin blood levels are increased (see section 5.2).
Ketoconazole: Repeated 200 mg daily dosing of ketoconazole, for seven days resulted in a 2.1 fold increase in Cmaxand a 2.5 fold increase in exposure of alfuzosin 10 mg OD when administered under fed conditions. Other parameters such as tmaxand t1/2were not modified.
The increase in alfuzosin Cmaxand AUC(last) following repeated 400 mg daily administration of ketoconazole was 2.3-fold, and 3.2-fold, respectively (see section 5.2).
See also section 4.4.
.4.6Fertility, pregnancy and lactation
Not relevant.
.4.7Effects on ability to drive and use machines
There are no data available on reduced reaction ability.
Adverse reactions such as dizziness and asthenia may occur essentially at the beginning of treatment. This has to be taken into consideration when driving vehicles and operating machines.
.4.8Undesirable effects
The most commonly reported event is dizziness, which occurs in approximately 5% of treated patients.
Classification of expected frequencies:
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)
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Blood and lymphatic system disorders |
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Not known |
Neutropenia, thrombocytopenia |
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Cardiac disorders |
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Common |
Postural hypotension (initially above all with too high a dose or if treatment is started again after a short interruption of therapy) (see section 4.4) |
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Uncommon |
Syncope (initially above all with too high a dose or if treatment is started again after a short interruption of therapy), tachycardia, palpitations |
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Very rare |
Angina pectoris predominantly in patients with pre-existing coronary heart disease (see section 4.4) |
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Not known |
Atrial fibrillation |
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Nervous system disorders |
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Common |
Vertigo, dizziness, malaise, headache |
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Uncommon |
Drowsiness |
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Not known |
Cerebral ischemic disorders in patients with underlying cerebrovascular disturbances (see section 4.4) |
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Eye disorders |
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Uncommon |
Vision abnormal |
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Not known |
Intraoperative floppy iris syndrome (see section 4.4) |
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Respiratory, thoracic and mediastinal disorders |
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Uncommon |
Rhinitis |
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Gastrointestinal disorders |
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Common |
Abdominal pain , diarrhoea, nausea, dryness of the mouth |
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Uncommon |
Vomiting, dyspepsia |
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Renal and urinary disorders: |
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Uncommon |
Urinary incontinence |
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Skin and subcutaneous tissue disorders |
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Uncommon |
Rash (urticaria, exanthema), pruritus |
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Very rare |
Angioedema |
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General disorders and administration site conditions |
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Common |
Asthenia |
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Uncommon |
Hot flushes, oedema, chest pain |
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Hepatobiliary disorders |
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Not known |
Hepatocellurar injury, cholestatic liver disease |
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Reproductive system and breast disorders |
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Not known |
Priapism |
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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 listed in [To be completed nationally].
.4.9Overdose
In case of overdose, conventional treatment such as addition of fluids and vasopressor drugs should take place in a hospital. The patient should be kept in the supine position.
In case of significant hypotension, the appropriate corrective treatment may be a vasoconstrictor that acts directly on vascular muscle fibers.
Alfuzosin is not easily dialysable because of its high degree of protein binding. Active charcoal should be administered following possible gastric lavage.
5Pharmacological Properties
.5.1Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in benign prostatic hypertrophy. ATC code : G04CA01
Alfuzosin,which is a racemate, isan oral quinazoline derivative, which selectively blocks post synaptic alpha‑1‑receptors. In vitrostudies have confirmed the selectivity of the substance on alpha‑1‑receptors in the trigone of the urine bladder, urethra and prostate. The clinical symptoms in benign prostatic hyperplasia are not only related to the size of the prostate, but also to the sympathomimetic nerve impulse, which by stimulating the post synaptic alpha receptors increase the tension of the smooth muscles of the lower urinary tract. During treatment with alfuzosin, smooth muscles are relaxed and thus urine flow is improved.
Clinical evidence of uroselectivity has been demonstrated by clinical efficacy and good safety profile in men treated with alfuzosin, including older people and hypertensive men.
In man, alfuzosin improves voiding parameters by reducing urethral tone and bladder outlet resistance, and facilitates bladder emptying.
A lower frequency of acute urinary retention is observed in the alfuzosin treated patient than in the untreated patient.
In placebo controlled studies in BPH patients, alfuzosin:
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significantly increases peak flow rate (Qmax) in patients with Qmax <15 ml/s by a mean of 30%. This improvement is observed from the first dose.
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significantly reduces the detrusor pressure and increases the volume producing a strong desire to void.
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significantly reduces the residual urine volume.
These urodynamic effects lead to an improvement of lower urinary tract symptoms i.e. filling (irritative) as well as voiding (obstructive) symptoms (LUTS = Lower Urinary Tract Symptoms) which was clearly demonstrated.
Paediatric population
Xatral is not indicated for use in the paediatric population (see section 4.2).
Efficacy of alfuzosin hydrochloride was not demonstrated in the two studies conducted in 197 patients 2 to 16 years of age with elevated detrusor leak point pressure (LPP≥40 cm H2O) of neurologic origin. Patients were treated with alfuzosin hydrochloride 0.1 mg/kg/day or 0.2 mg/kg/day using adapted paediatric formulations.
.5.2Pharmacokinetic properties
Alfuzosin
Alfuzosin shows linear kinetics in the therapeutic dosage area. Bioavailability is 64% when administered as an immediate release formulation (2.5 mg). Maximal plasma concentration is reached within 0.5‑6 hours after administered dose. The kinetic profile is characterised by large interindividual fluctuations (sevenfold)in plasma concentrations. Plasma half-life is approximately 5 hours (1‑10 hours). The pharmacokinetic profile is not altered when alfuzosin is administered with food.
Plasma protein binding is about 90%. Alfuzosin is eliminated by metabolism, renal excretion and probably also biliar excretion. After extensive metabolism by the liver the majority of the metabolites are recovered in faeces (75% to 91%). CYP3A4 is the main hepatic enzyme isoform involved in the metabolism of alfuzosin (see section 4.5). None of the metabolites has any pharmacological activity.
Volume of distribution and clearance is increased in reduced renal function, possibly due to decreased protein binding capacity. Half‑life is however unchanged. In patients with severe hepatic insufficiency, the elimination half-life is prolonged. A two-fold increased in Cmaxand three-fold increase in AUC is observed. Bioavailability is increased in comparison to that in healthy volunteers.
Older people have higher bioavailability, which leads to higher maximum plasma concentrations but unchanged half-life.
Prolonged-release tablets 5 mg: Maximum plasma concentration is reached approximately 3 hours (1‑4 hours) after the administered dose. Half‑life is 8 hours (5-13 hours). The bioavailability of prolonged-release tablets 5 mg is reduced by an average of 15% as compared to Xatral 2.5 mg film-coated tablets.
.5.3Preclinical safety data
Non-clinical data reveal no special hazard for humans.
6Pharmaceutical Particulars
.6.1List of excipients
Film-coated tablet 2.5 mg:
lactose
microcrystalline cellulose
povidone
sodium starch glycollate
magnesium stearate
hypromellose
macrogol 400
titanium dioxide (E 171)
Prolonged-release tablet 5 mg:
microcrystalline cellulose
calcium hydrogen phosphate dihydrate
hydrogenated castor oil
povidone
magnesium stearate
hypromellose
propylene glycol
titanium dioxide (E 171)
red and yellow iron oxide (E 172)
.6.2Incompatibilities
Not applicable.
.6.3Shelf life
Film-coated tablets 2.5 mg: 3 years.
Prolonged-release tablets 5 mg: 3 years.
.6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
.6.5Nature and contents of container
Film-coated tablets 2.5 mg: 30’s (blister PVC/aluminium pack). Not marketed at present.
Prolonged-release tablets 5 mg: 28´s, 56´s, 60´s, 180´s (blister PVC/aluminium pack). Not all pack sizes may be marketed.
.6.6Special precautions for disposal
No special requirements.
7Marketing Authorisation Holder
[To be completed nationally]
8MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9Date of First Authorisation/Renewal of the Authorisation
Xatral Film-coated tablets 2.5 mg:
Date of first authorisation: 19 December 1994
Date of latest renewal: 01 June 2009
Xatral Prolonged-release tablets 5 mg:
Date of first authorisation: 19 December 1994
Date of latest renewal: 01 June 2009
10Date of Revision of the Text
11 July 2014
Detailed information on this product is available on the website of: Medical Products Agency