Alfuzosin Hydrochloride 2.5mg Tablets

Each tablet contains 2.5mg alfuzosin hydrochloride.

Excipients:

Each tablet contains 61 mg lactose anhydrous.

For a full list of excipients, see section 6.1.

Film-coated tablets.

White round, film coated tablet for oral administration marked Xatral 2.5 on one side.

Treatment of the functional symptoms of benign prostatic hypertrophy.

Alfuzosin Hydrochloride 2.5mg 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 Alfuzosin Hydrochloride 2.5mg Tablets 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 Alfuzosin Hydrochloride 2.5mg Tablets/day to be increased to Alfuzosin Hydrochloride 2.5mg Tablets twice daily according to clinical response.

Lactose

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

• Hypersensitivity to the active substance or to any of the excipients (see section 6.1 List of excipients).

• History of orthostatic hypotension.

• Combination with other alpha-1 receptorblockers.

• Severe hepatic insufficiency.

Warnings

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 withalpha1-blockers.Although the risk of this event with alfuzosin appears very low, ophthalmic surgeons should be informed in advance of cataract surgery of current or part use of alpha-1-blockers, as IFIS may lead to increased procedural complications. Care should be taken when alfuzosin is administered to patients who have had a pronounced hypotensive response to another alpha1-blocker.

As with all alpha-1 blockers, in some subjects, in particular patients receiving antihypertensive medications or nitrates, 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.

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.

Precautions

Treatment should be initiated gradually in patients with hypersensitivity to alpha-1-blockers. Alfuzosin Hydrochloride 2.5mg Tablets 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 Alfuzosin Hydrochloride 2.5mg Tablets should be discontinued.

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

Combinations contraindicated:

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

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 blood levels are increased.

The administration of general anaesthetics to patients receiving Alfuzosin Hydrochloride 2.5mg Tablets could cause profound hypotension. It is recommended that Alfuzosin Hydrochloride 2.5mg 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 essentially at the beginning of treatment. 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).

• Cardiac disorders

Uncommon: tachycardia, palpitations

Very rare: angina pectoris in patients with pre-existing coronary artery disease (see section 4.4.)

Not known: atrial fibrillation

• Eye disorders

Uncommon: vision abnormal

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

• General disorders and administration site conditions

Common: asthenia, malaise

Uncommon:, oedema, chest pain

• Gastro-intestinal disorders

Common: nausea, abdominal pain, diarrhoea, dry mouth

Not known: vomiting

• Hepatobiliary disorders

Not known: hepatocellular injury, cholestatic liver disease

• Nervous system disorders

Common: faintness/dizziness, vertigo, headache

Uncommon: drowsiness, syncope

• Reproductive system and breast disorders

Not known: priapism

• Respiratory, thoracic and mediastinal disorders

Uncommon: rhinitis

• Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Very rare: urticaria, angiœdema

• Vascular disorders

Common: hypotension (postural)

Uncommon: flushing

• Blood and lymphatic system disorders

Not known: neutropenia

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

Pharmacotherapeutic group: alpha adrenoreceptor antagonists

ATC code: G04C A01

Alfuzosin is an orally active quinazoline derivative. It is a selective, peripherally acting antagonist of post synaptic 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 alpha-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 less than or equal to 15ml/s by a mean of 30 percent. 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.

Alfuzosin Hydrochloride 2.5mg Tablets are 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 inter-individual 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 Alfuzosin Hydrochloride 2.5mg Tablets 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.

Not known.

3 years.

Do not store above 30ºC. Store in the original package

Boxes with 30, 60 or 90 tablets in pvc/foil blister strips.

PP containers with 30, 60, 90 tablets.

Not all pack sizes may be marketed.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

PL 17780/0220

31^st July 2007

08 March 2011