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SANOFI

Citywest Business Campus, Dublin 24, Ireland
Telephone: +353 1 4035600
Fax: +353 1 4035687
Medical Information e-mail: iemedinfo@sanofi.com


Summary of Product Characteristics last updated on medicines.ie: 21/06/2013
SPC Xatral 10mg Prolonged Release Tablets



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1. NAME OF THE MEDICINAL PRODUCT

Xatral 10mg Prolonged Release Tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10mg alfuzosin hydrochloride.

For a full list of excipients, see Section 6.1.


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3. PHARMACEUTICAL FORM

Tablet, prolonged release.

Round biconvex three layer tablet: one white layer between two yellow layers.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Treatment of the functional symptoms of benign prostatic hypertrophy.

Adjunctive therapy with urethral catheterisation for Acute Urinary Retention related to BPH.


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4.2 Posology and method of administration

Xatral 10mg prolonged release tablets are for oral administration.

Xatral 10mg Prolonged Release Tablets should be swallowed whole.

BPH: The recommended dose is one 10mg tablet once daily to be taken after a meal.

AUR: One 10mg tablet daily after a meal to be taken from the first day of catheterisation.

Paediatric population:

Efficacy of Xatral has not been demonstrated in children aged 2 to 16 years (see section 5.1). Therefore, Xatral is not indicated for use in paediatric population.


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4.3 Contraindications

• Hypersensitivity to alfuzosin or any component.

• History of orthostatic hypotension.

• Combination with other alpha1-blockers.

• Hepatic insufficiency.


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4.4 Special warnings and precautions for use

As with all alpha1-blockers in some subjects, in particular patients receiving antihypertensive medications or nitrates. In some subjects postural hypotension may develop, with or without symptoms (dizziness, fatigue, sweating) within a few hours following administration. These effects are usually transient, occur at the beginning of treatment and do not usually prevent the continuation of treatment. In such cases, the patient should lie down until the symptoms have completely disappeared.

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 patient should be warned of the possible occurrence of such events.

Care should be taken when alfuzosin is administered to patients who have had a pronounced hypotensive response to another alpha1-blocker. Blood pressure should be monitored regularly, especially at the beginning of treatment.

Care should be taken when Xatral is administered to patients with symptomatic orthostatic hypotension or in patients on anti-hypertensive medication or nitrates.

In patients with coronary insufficiency, specific therapy for coronary insufficiency should be continued. If angina pectoris reappears or worsens alfuzosin should be discontinued.

As with all alpha1-receptor 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.

Alfuzosin 10 mg prolonged release tablets contain hydrogenated castor oil which may cause stomach upset and diarrhoea.

As there are no clinical safety data available in patients with severe renal impairment (creatinine clearance < 30ml/min), alfuzosin 10 mg prolonged-release tablets should not be administered to this patient group.

Patients should be warned that the tablet should be swallowed whole. Any other mode of administration, such as crunching, crushing, chewing, grinding or pounding to powder should be prohibited. These actions may lead to inappropriate release and absorption of the drug and therefore possible early adverse reactions.


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4.5 Interaction with other medicinal products and other forms of interaction

Combinations contra-indicated:

• Alpha1-receptor blockers (see section 4.3)

Combinations to be taken into account:

• Antihypertensive drugs (see section 4.4 Special Warnings and Precautions for Use)

• Nitrates (see section 4.4 Special Warnings and Precautions for Use)

• Potent CYP3A4 inhibitors, such as ketoconazole, itraconazole and ritonavir since alfuzosin blood levels are increased (see section 5.2)

Concomitant use with other alpha1-receptor blockers should be avoided and antihypertensive agents should be used with caution because of the risk of a hypotensive effect.

The administration of general anaesthetics to patients treated with alfuzosin may lead to blood pressure instability. It is recommended that the tablets be withdrawn 24 hours before surgery.


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4.6 Pregnancy and lactation

Due to the type of indication this section is not applicable.


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4.7 Effects on ability to drive and use machines

There are no data available on the effect on driving vehicles. Adverse reactions such as vertigo, dizziness and asthenia may occur. Some subjects particularly those on antihypertensive medication may experience postural hypotension, which may or may not result in symptoms such as dizziness and fatigue.This has to be taken into account when driving vehicles and operating machinery.


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4.8 Undesirable effects

Classification of expected frequencies:

Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data)

 

Very common

(≥1/10)

Common

(≥1/100 to <1/10

Uncommon

(≥1/1000 to <1/100)

Rare

(≥1/10000 to <1/1000

Very rare

(<1/10000)

Not known

(cannot be estimated from the available data)

Cardiac disorders

  

Tachycardia

 

Angina pectoris in patients with pre-existing coronary artery disease

Atrial fibrillation

Eye disorders

     

Intraoperative floppy iris syndrome

General disorders and administration site conditions

 

Asthenia

Oedema, chest pain

   

Gastrointestinal disorders

 

Nausea, abdominal pain,

Diarrhoea

  

Vomiting

Hepatobiliary disorders

     

hepatocellular injury, cholestatic liver disease

Nervous system disorders

 

Faintness/dizziness, headache

Syncope, vertigo

   

Reproductive system and breast disorders

     

Priapism

Respiratory, thoracic and mediastinal disorders

  

Rhinitis

   

Skin and subcutaneous tissue disorders

  

Rash, pruritus

 

Urticaria, angiodema

 

Vascular disorders

  

Flushing, Hypotension (postural)

   

Blood and lymphatic system disorders

     

Neutropenia,thrombocytopenia


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4.9 Overdose

In case of overdosage, the patient should be hospitalised, kept in the supine position, and conventional treatment of hypotension should take place.

In case of significant hypotension, the appropriate corrective treatment may be a vasoconstrictor that acts directly on vascular muscle fibres

Alfuzosin is highly protein-bound; therefore, dialysis may not be of benefit.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Alfuzosin is an orally active quinazoline derivative. It is a selective, peripherally acting antagonist of postsynaptic alpha1-adrenoceptors.

In vitro pharmacological studies have documented the selectivity of alfuzosin for the alpha1-adrenoreceptors located in the prostate, bladder base and prostatic urethra.

Clinical manifestations of Benign Prostatic Hypertrophy are associated with infra vesical obstruction which is triggered by both anatomical (static) and functional (dynamic) factors. The functional component of obstruction arises from the tension of prostatic smooth muscle which is mediated by alpha1-adrenoceptors. Activation of alpha1-adrenoceptors stimulates smooth muscle contraction, thereby increasing the tone of the prostate, prostatic capsule, prostatic urethra and bladder base, and, consequently, increasing the resistance to bladder outflow. This in turn leads to outflow obstruction and possible secondary bladder instability.

Alpha-blockade decreases infra vesical obstruction via a direct action on prostatic smooth muscle.

In vivo, animal studies have shown that alfuzosin decreases urethral pressure and therefore, resistance to urine flow during micturition. Moreover, alfuzosin inhibits the hypertonic response of the urethra more readily than that of vascular muscle and shows functional uroselectivity in conscious normotensive rats by decreasing urethral pressure at doses that do not affect blood pressure.

In man, alfuzosin improves voiding parameters by reducing urethral tone and bladder outlet resistance, and facilitates bladder emptying.

In placebo controlled studies in BPH patients, alfuzosin:

• significantly increases peak flow rate (Qmax) in patients with Qmax ≤ 15ml/s by a mean of 30%. This improvement is observed from the first dose,

• significantly reduces the detrusor pressure and increases the volume producing a strong desire to void,

• significantly reduces the residual urine volume.

In addition, the efficacy on peak flow rate is maintained up to 24 hours after intake.

These favourable urodynamic effects lead to an improvement of lower urinary tract symptoms i.e. filling (irritative) as well as voiding (obstructive) symptoms.

Alfuzosin may cause moderate antihypertensive effects.

A lower frequency of acute urinary retention is observed in the alfuzosin treated patient than in the untreated patient. In addition, alfuzosin significantly increases the success rate of spontaneous voiding after catheter removal in men with an episode of AUR related to BPH.

Paediatric population

Alfuzosin 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.


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5.2 Pharmacokinetic properties

Prolonged-release formulation:

The mean value of the relative bioavailability is 104.4 % versus the immediate release formulation (2.5 mg tid) in middle-aged healthy volunteers and the maximum plasma concentration is being achieved 9 hours after administration compared to 1 hour for the immediate release formulation.

The apparent elimination half-life is 9.1 hours.

Studies have shown that consistent pharmacokinetic profiles are obtained when the product is administered after a meal.

Under fed conditions, mean Cmax and Ctrough values are 13.6 (SD=5.6) and 3.2 (SD=1.6) ng/ml respectively. Mean AUC 0-24 is 194 (SD=75) ng.h/ml. A plateau of concentrations is observed from 3 to 14 hours with concentrations above 8.1ng/ml (Cav) for 11 hours.

Compared to healthy middle aged volunteers, the pharmacokinetic parameters (Cmax and AUC) are not increased in elderly patients.

Compared to subjects with normal renal function, mean Cmax and AUC values are moderately increased in patients with renal impairment, without modification of the apparent elimination half-life. This change in the pharmacokinetic profile is not considered clinically relevant. Therefore, this does not necessitate a dosing adjustment.

The binding of alfuzosin to plasma proteins is about 90%. Alfuzosin undergoes extensive metabolism by the liver, with only 11 % of the parent compound being excreted unchanged in the urine. The majority of the metabolites (which are inactive) are excreted in the faeces (75 to 91 %).

The pharmacokinetic profile of alfuzosin is not affected by chronic cardiac insufficiency.

Metabolic interactions: CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. Ketoconazole is a strong-potency inhibitor of CYP3A4. Repeated 200 mg daily dosing of ketoconazole, for seven days resulted in an increase of the Cmax (2.11-fold) and AUClast (2.46-fold) of alfuzosin 10 mg OD under fed conditions. Other parameters such as tmax and t1/2Z were not modified. The 8-day repeated administration of ketoconazole 400 mg daily increased Cmax of alfuzosin by 2.3-fold, AUClast and AUC by 3.2 and 3.0, respectively (see section 4.5)


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5.3 Preclinical safety data

No data of therapeutic relevance.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Ethylcellulose

Hydrogenated castor oil

Hypromellose

Yellow ferric oxide

Magnesium stearate

Microcrystalline cellulose

Povidone

Silica colloidal hydrated

Mannitol.


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

Blister strips: 3 years

Polyethylene containers: 2 years


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6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.


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6.5 Nature and contents of container

Boxes with 10 or 30 tablets in PVC/foil blister strips or polyethylene containers.


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6.6 Special precautions for disposal and other handling

No special requirements


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7. MARKETING AUTHORISATION HOLDER

sanofi-aventis Ireland Ltd. T/A SANOFI

Citywest Business Campus

Dublin 24

Ireland


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8. MARKETING AUTHORISATION NUMBER(S)

PA 540/162/3


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26th May 2000

Date of last renewal: 1st July 2009


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10. DATE OF REVISION OF THE TEXT

14 June 2013



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Active Ingredients

 
   alfuzosin hydrochloride