Xatral XL 10 mg prolonged release tablets

Each tablet contains 10mg alfuzosin hydrochloride.

Excipient: Hydrogenated castor oil

For a full list of excipients, see section 6.1

Prolonged release tablet.

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

Treatment of the functional symptoms of benign prostatic hypertrophy (BPH).

For information on use in acute urinary retention (AUR) related to BPH see sections 4.2 and 5.1.

Xatral XL should be swallowed whole (see section 4.4).

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

AUR: In patients 65 years and older, one 10 mg tablet daily after a meal to be taken from the first day of catheterisation. The treatment should be administered for 3-4 days, 2-3 days during catheterisation and 1 day after its removal. In this indication no benefit has been established in patients under 65 years of age or if treatment is extended beyond 4 days.

Hypersensitivity to the active substance or to any of the excipients. History of orthostatic hypotension. Combination with other alpha-blockers. Hepatic insufficiency.

As with all alpha-1-blockers in some subjects, in particular patients receiving antihypertensive medications, postural hypotension with or without symptoms (dizziness, fatigue, sweating) may develop within a few hours following administration. In such cases, the patient should lie down until the symptoms have completely disappeared.

These effects are transient and do not usually prevent the continuation of treatment after adjustment of the dose. The patient should be warned of the possible occurrence of such events.

Treatment should be initiated gradually in patients with hypersensitivity to alpha-1-blockers. Xatral XL should be administered carefully to patients being treated with antihypertensives. Blood pressure should be monitored regularly, especially at the beginning of treatment.

In patients with coronary insufficiency specific anti-anginal therapy should be continued, but if the angina reappears or worsens Xatral XL should be discontinued.

Experience in patients with severe renal impairment is limited and cautious use in these patients is recommended.

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.

The excipient hydrogenated castor oil may cause stomach upset and diarrhoea.

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.

Combinations contra-indicated:

• Alpha-1-receptor blockers (see section 4.3).

Combinations to be taken into account:

• Antihypertensive drugs (see section 4.4).

• Nitrates

• potent CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir.

Repeated 200 mg daily dosing of ketoconazole, for seven days resulted in a 2.1-fold increase in Cmax and a 2.5-fold increase in exposure of alfuzosin 10 mg when administered as a single dose under fed conditions (high fat meal). Other parameters such as tmax and t_1/2 were not modified.

Cmax and AUC of alfuzosin 10 mg, when administered as a single dose under fed conditions, increased 2.3- fold and 3.0- fold, respectively following 8-day repeated 400 mg ketoconazole daily dosing i (see section 5.2).

The administration of general anaesthetics to patients receiving Xatral XL could cause profound hypotension. It is recommended that the tablets be withdrawn 24 hours before surgery.

Other forms of interaction

No pharmacodynamic or pharmacokinetic interaction has been observed in healthy volunteers between alfuzosin and the following drugs: warfarin, digoxin, hydrochlorothiazide and atenolol.

Due to the type of indication this section is not applicable

There are no data available on the effect on driving vehicles. Adverse reactions such as vertigo, dizziness and asthenia may occur. This has to be taken into account when driving vehicles and operating machinery.

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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

•Nervous system disorders

Common: faintness/dizziness, headache

Uncommon: vertigo, malaise, drowsiness

•Eye disorders

Uncommon: vision abnormal

Not known: intraoperative floppy iris syndrome (see section 4.4)

•Cardiac disorders

Uncommon: tachycardia, palpitations, hypotension (postural), syncope

Very rare: New onset, aggravation or recurrence of angina pectoris in patients with pre-existing coronary artery disease. (see section 4.4.)

•Respiratory , thoracic and mediastinal disorders

Uncommon: rhinitis

•Gastro-intestinal disorders

Common: nausea, abdominal pain

Uncommon: diarrhoea, dry mouth, vomiting

•Hepatobiliary disorders

Not known: hepatocellular injury, cholestatic liver disease.

•Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Very rare: urticaria, angioedema

•General disorders and administration site conditions

Common: asthenia

Uncommon: flushes, oedema, chest pain

Although only reported in isolated cases with alfuzosin, occurrence of priapism can not be excluded as it is generally accepted as being attributable to all other alpha adrenoreceptor blockers.

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

Alfuzosin is not dialysable because of its high degree of protein binding.

Pharmacotherapeutic group: alpha-adrenoreceptor antagonists

ATC code: G04CA01

Alfuzosin is an orally active quinazoline derivative. It is a selective, peripherally acting antagonist of postsynaptic alpha-1-adrenoceptors.

In vitro pharmacological studies have documented the selectivity of alfuzosin for the alpha-1-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 alpha-adrenoceptors. Activation of alpha-1-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.

These favourable urodynamic effects lead to an improvement of lower urinary tract symptoms ie. 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.

AUR (related to BPH):

In the ALFAUR study, the effect of alfuzosin on the return of normal voiding was evaluated in 357 men over 50 years, presenting with a first episode of acute urinary retention (AUR), related to BPH. In this multicentre, randomised double blind parallel group study comparing alfuzosin 10mg/day and placebo, the evaluation of voiding was performed 24 hours after catheter removal, the morning after 2-3 days of treatment.

In men aged 65 years and over alfuzosin significantly increased the success rate of spontaneous voiding after catheter removal – see table. No benefit has been established in patients under 65 years of age or if treatment is extended beyond 4 days.

ALFAUR study: Percentage of patients (ITT population) successfully voiding post-catheter removal

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 concentration is observed from 3 to 14 hours with concentrations above 8.1 ng/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 main hepatic enzyme isoform involved in the metabolism of alfuzosin (see section 4.5)

No data of therapeutic relevance.

Ethylcellulose

Hydrogenated Castor Oil

Hypromellose

Yellow Ferric Oxide (E172)

Magnesium Stearate

Microcrystalline Cellulose

Povidone

Silica Colloidal Hydrated

Mannitol.

None known.

3 years.

No special precautions for storage.

Store in the original container.

Boxes with 10 and 30 tablets in pvc/foil blister strips.

No special requirements

Sanofi-aventis

One Onslow Street

Guildford

Surrey, GU1 4YS, UK

PL 04425/0657

02 April 2009

April 2009

POM