Xatral 2.5 mg film coated tablet

Each tablet contains 2.5mg alfuzosin hydrochloride.

Excipient: Lactose

For a full list of excipients, see section 6.1

Film coated tablet.

White round tablet marked Xatral 2.5 on one side.

Treatment of the functional symptoms of benign prostatic hypertrophy.

Xatral tablets should be swallowed whole. The first dose should be given just before bedtime.

Adults

The usual dose is one tablet three times daily. The dose may be increased to a maximum of 4 tablets (10mg) per day depending on the clinical response.

Elderly and treated hypertensive patients

As a routine precaution when prescribing alfuzosin to elderly patients (aged over 65 years) and the treated hypertensive patient, the initial dose should be 1 tablet in the morning and 1 tablet in the evening.

Renal insufficiency

In patients with renal insufficiency, as a precaution, it is recommended that the dosing be started at Xatral 2.5mg twice daily adjusted according to clinical response.

Hepatic insufficiency

In patients with mild to moderate hepatic insufficiency, it is recommended that therapy should commence with a single dose of Xatral 2.5mg/day to be increased to Xatral 2.5mg twice daily according to clinical response.

Hypersensitivity to the active substance or any of the excipients. History of orthostatic hypotension. Combination with other α-blockers. Severe 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 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 should be discontinued.

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

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 contraindicated:

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

Combinations to be taken into account:

- Antihypertensive drugs (see section 4.4.2)

- 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 (see section 5.2)

The administration of general anaesthetics to patients receiving Xatral could cause profound hypotension. It is recommended that Xatral 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, vertigo, malaise, headache

Uncommon: drowsiness

• Eye disorders

Uncommon: vision abnormal

Unknown: intraoperative floppy iris syndrome

• Cardiac disorders

Common: hypotension (postural)

Uncommon: tachycardia, palpitations, 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, diarrhoea, dry mouth

• 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 hospitalised, kept in the supine position, and conventional treatment of hypotension should take place.

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

Alfuzosin is an orally active quinazoline derivative. It is a selective, peripherally acting antagonist of post synaptic α₁-adrenoceptors.

Pharmacotherapeutic group: alpha-adrenoreceptor antagonists

ATC code: G04CA01

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 α-adrenoceptors. Activation of α₁-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.

Xatral is well absorbed with a mean bioavailability of 64%, peak plasma levels are generally reached in 0.5-3 hours. Kinetics within the therapeutic range are linear. The kinetic profile is characterised by large interindividual fluctuations in plasma concentrations. The terminal half-life is 3-5 hours. Alfuzosin is 90% protein bound in plasma, 68.2% to human serum albumin and 52.5% to human serum alpha-glycoprotein. It is partially metabolised and excreted mainly in the bile and faeces.

None of the metabolites found in man has any pharmacodynamic activity. The pharmacokinetic profile is not affected by taking Xatral with food.

In subjects over 75 years, absorption is more rapid and peak plasma levels are higher. Bioavailability may be increased and in some patients the volume of distribution is reduced. The elimination half-life does not change.

The volume of distribution and clearance of alfuzosin are increased in renal insufficiency, with or without dialysis, owing to an increase in the free fraction. Chronic renal insufficiency even when severe (creatinine clearance between 15 and 40 mls/min) is not adversely affected by alfuzosin.

In patients with severe hepatic insufficiency, the elimination half-life is prolonged. A two-fold increase in Cmax values and a three-fold increase in the AUC is observed. Bioavailability is increased compared with healthy volunteers.

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 (see section 4.5)

No data of therapeutic relevance.

Tablet core:

Microcrystalline Cellulose

Lactose

Povidone

Sodium Starch Glycollate

Magnesium Stearate

Coating:

Methylhydroxypropylcellulose

Macrogol 400

Titanium Dioxide (E171)

Not known.

3 years.

Store in a dry place at or below 30°C.

Boxes with 60 tablets in pvc/foil blister strips.

No special requirements

Sanofi-aventis

One Onslow Street

Guildford

Surrey,

GU1 4YS

PL 04425/0655

09^th February 2009

February 2009

POM