Consumer medicine information

Xatral SR

Alfuzosin hydrochloride

BRAND INFORMATION

Brand name

Xatral SR Prolonged release tablets

Active ingredient

Alfuzosin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xatral SR.

What is in this leaflet

This leaflet answers some common questions about Xatral SR tablets.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Xatral is used for

Xatral belongs to a group of medicines called alpha1-receptor blockers.

Xatral is used to treat a medical condition in men called Benign Prostatic Hyperplasia or BPH. BPH is a condition where the prostate gland (which is near your bladder) has become bigger making it more difficult for you to pass urine. This can lead to symptoms such as:

  • Weak or interrupted stream of urine
  • Feeling that you cannot empty your bladder completely
  • Delay before you start to pass urine
  • Needing to pass urine often, especially at night
  • Feeling that you must pass urine right away.

Xatral works by relaxing the muscles in the prostate gland and increasing the flow of urine.

Your doctor, however, may prescribe Xatral for another purpose.

Ask your doctor or pharmacist if you have any questions about why it has been prescribed for you.

This medicine is only available with a doctor's prescription.

There is no evidence that this medicine is addictive.

Before you take it

When you must not take it

Do not take Xatral if you have liver disease.

Do not take Xatral if you are currently taking another alpha-blocker.

These include prazosin (Minipress), terazosin (Hytrin) and tamsulosin (Flomaxtra).

Do not take Xatral if you are currently taking potent CYP3A4 inhibitors (medicines used to treat infections)

These include ketoconazole (Nizoral), itraconazole (Sporanox) and ritonavir (Norvir)

Do not take Xatral if you have a history of feeling dizzy, tired or sweating on standing (orthostatic hypotension).

Do not take Xatral if you are allergic to it or any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Xatral is not intended for use in women.

Do not give Xatral to a child or adolescent.

There is no experience with its use in children or adolescents under 18 years old.

Do not take it after the expiry date (EXP) printed on the pack.

If you take it after the expiry date has passed, it may not work as well.

Do not take it if the packaging is damaged or shows signs of tampering.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any of the ingredients listed at the end of this leaflet
  • any other alpha-blockers, including prazosin (Minipress), terazosin (Hytrin) and tamsulosin (Flomaxtra)
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • angina (a feeling of pain, tightness, heaviness or pressure in the chest)
  • Parkinson's disease
  • multiple sclerosis
  • heart failure
  • prostate cancer
  • high blood pressure
  • heart conditions or heart problems
  • you are taking medicines used to treat a fast or irregular heart beat e.g. amiodarone, quinidine, disopyramide

Tell your doctor or pharmacist if you plan to have surgery.

If you have not told your doctor or pharmacist about any of the above, tell them before you take Xatral.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food store.

Xatral and some other medications may interfere with each other. These include:

  • medicines to lower blood pressure
  • other alpha-blockers, including prazosin (Minipress), terazosin (Hytrin) and tamsulosin (Flomaxtra)
  • non-selective alpha-blockers, including phentolamine (Regitine), labetalol (Trandate) and phenoxybenzamine (Dibenyline)
  • nitrates (medicines which aid the dilation of constricted blood vessels)
  • potent CYP3A4 inhibitors (medicines used to treat infections) such as ketoconazole (Nizoral), itraconazole (Sporanox) and ritonavir (Norvir)
  • general anaesthetics (medicines used to put you to sleep during an operation or procedure).

These medicines may be affected by Xatral, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines. Your doctor or pharmacist will advise you.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking Xatral.

How to take it

How much to take

The standard dose for this medicine is one tablet taken once each day.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how many to take.

Follow the instructions they give you.

If you take the wrong dose, Xatral may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

Do not divide, crush or chew the tablets.

If they are broken or crushed they will not work over 24 hours as they are supposed to and it may increase the risk of side effects.

When to take it

Take Xatral after a meal, at about the same time each day.

Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

If you are not sure when to take it, ask your doctor or pharmacist.

How long to take it

Continue taking your medicine for as long as your doctor or pharmacist tells you.

Do not stop taking the tablets suddenly or allow your tablets to run out.

If you need to stop taking Xatral your doctor will slowly reduce the dose over a number of days or weeks.

Ask your doctor or pharmacist if you are not sure how long to take the medicine for.

If you forget to take it

Do not try to make up for missed doses by taking more than one dose at a time.

This may increase the chance of getting an unwanted side effect.

If it is almost time for your next dose (within 12 hours), skip the dose you missed and take the next dose when you are meant to.

Do not take a double dose to make up for the dose you have missed.

Otherwise take it as soon as you remember, and then go back to taking it as you would normally.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Xatral.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much Xatral, you may feel light-headed, dizzy, tired, drowsy or sweaty.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Xatral.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Xatral.

If you are undergoing eye surgery because of cataract (cloudiness of the lens) please inform your eye specialist before the operation that you are using or have previously used Xatral.

This is because Xatral may cause complications during the surgery which can be managed if your specialist is prepared in advance.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine.

In most cases, Xatral will need to be stopped before surgery.

Things you must not do

Do not take more than the recommended dose unless your doctor or pharmacist tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking Xatral, or lower the dosage, without checking with your doctor or pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how Xatral affects you.

It may cause dizziness, light-headedness, tiredness or weakness in some people, especially after the first dose or after a dose increase. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you feel dizzy.

It is recommended that you do not drink alcohol while taking Xatral.

The effects of alcohol (dizziness or light-headedness) could be made worse while taking Xatral.

Get up slowly after you have been sitting or lying down.

Xatral may cause dizziness, light-headedness and fainting, especially if you get up too quickly. This is also more likely to occur if you have just started Xatral or the dose has just been increased.

If you feel dizzy or light headed, lie down so that you do not faint. Then sit up for a few moments before standing to prevent the dizziness from returning.

If the symptoms continue, tell your doctor or pharmacist.

Side effects

All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor or pharmacist has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Xatral.

It helps most people with BPH, but it may have unwanted side effects in a few people.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • faintness or dizziness
  • headaches
  • sweating or flushes
  • nausea or vomiting
  • stomach pain or diarrhoea
  • dry mouth
  • tiredness, drowsiness or weakness
  • inflammation or irritation of the nose
  • oedema (swelling).

These are mild side effects of this medicine and are usually short-lived.

Tell your doctor or pharmacist immediately if you notice any of the following:

  • irregular heart beat or palpitations
  • chest pain
  • yellowing of the skin or eyes
  • hives or severe skin reactions.
  • bleeding or bruising more easily than normal

These may be serious side effects of Xatral. You may need urgent medical attention. Serious side effects are uncommon.

If any of the following happen, stop taking this medicine and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth or throat, which may cause difficultly in swallowing or breathing.

These are very serious side effects. If you have them, you may have had a serious allergic reaction to Xatral. You may need urgent medical attention or hospitalisation.

These side effects are very rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

Other side effects not listed above may occur in some consumers.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

After taking it

If you have any queries about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor or pharmacist.

Storage

Keep your tablets in the blister pack until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Keep the medicine in a cool, dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill.

Do not leave it in the car.

Heat and damp can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking Xatral, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Xatral is three layered biconvex tablets: two of the layers are yellow with a white layer in-between.

Xatral is a sustained release preparation.

A blister pack contains 30 or 60 tablets.

Ingredients

Active Ingredient:
Alfuzosin hydrochloride 10mg

Inactive Ingredients:

  • ethylcellulose
  • hydrogenated castor oil
  • hypromellose
  • yellow iron oxide
  • magnesium stearate
  • microcrystalline cellulose
  • povidone
  • silicon dioxide
  • mannitol.

Xatral does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

Manufacturer/Sponsor

Xatral is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113

This leaflet was prepared in October 2017

Australian Register Number(s)
AUST R 81900

®Registered Trademark

xatral-sr-ccdsv13-cmiv7-oct17

BRAND INFORMATION

Brand name

Xatral SR Prolonged release tablets

Active ingredient

Alfuzosin hydrochloride

Schedule

S4

 

1 Name of Medicine

Alfuzosin hydrochloride.

2 Qualitative and Quantitative Composition

Xatral (alfuzosin hydrochloride) is an orally active quinazoline derivative.
Each tablet contains 10 mg of alfuzosin hydrochloride as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release tablet.
Three-layered, round biconvex, prolonged release tablet containing the active ingredient in a white matrix layer between two inactive yellow layers.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of the functional symptoms of benign prostatic hyperplasia.

4.2 Dose and Method of Administration

The recommended dose is one 10 mg tablet daily to be taken immediately after the meal. The tablets should be swallowed whole.

4.3 Contraindications

Xatral SR must not be administered to patients with known hypersensitivity to alfuzosin hydrochloride or any other ingredient in this product, to patients with a history of orthostatic hypotension or hepatic insufficiency.
Xatral SR is contraindicated in combination with other alpha-blockers.
Concomitant administration of Xatral SR with potent CYP3A4 inhibitors is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Xatral SR should be administered carefully to patients with known hypersensitivity to α1-blockers.
In certain subjects, in particular elderly patients and 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 symptoms have completely disappeared. These effects are usually transient, occur at the beginning of treatment and do not usually prevent the continuation of treatment. Pronounced drop in blood pressure has been reported in postmarketing surveillance in patients with pre-existing risk factors (such as underlying cardiac diseases and/or concomitant treatment with antihypertensive medication). The risk of developing hypotension and related adverse reactions may be greater in elderly patients. The patients should be warned about the possible occurrence of such events.
Xatral SR should be administered carefully to patients being treated with antihypertensives. Blood pressure should be monitored regularly, especially at the beginning of treatment.
Xatral SR should be administered carefully to patients who have had a pronounced hypotensive response to another α1-blocker.
Care should be taken when alfuzosin is administered to patients with symptomatic orthostatic hypotension or in patients on antihypertensive medication or nitrates.
Use with caution in patients with acquired or congenital QT prolongation or who are taking medications that prolong the QT interval.
Alfuzosin, like other alpha adrenergic antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Patients should be advised about the seriousness of this condition as it can lead to permanent impotence if not properly treated.
Xatral SR should not be prescribed alone in coronary patients: specific treatment for coronary insufficiency should be continued. If the angina reappears or worsens, Xatral SR should be discontinued.
Patients with Parkinson's disease, multiple sclerosis, unstable angina or severe heart failure were excluded from phase II studies. As a result, the safety of Xatral SR in these patients has not been formally assessed.
Carcinoma of the prostate should be excluded in any patients for whom alfuzosin therapy is being considered for presumed BPH.
Patients should be warned that the tablet should be swallowed whole. Any other mode of administration, such as crushing, chewing, grinding or pounding to powder should be avoided. These actions may lead to inappropriate release and absorption of the drug and therefore possible unwanted adverse effects.

Cataract surgery.

The 'intraoperative floppy iris syndrome' (IFIS) has been observed during cataract surgery in some patients on, or previously treated with, tamsulosin. Isolated reports have also been received with other α1-blockers and the possibility of a class effect cannot be excluded. This variant of small pupil syndrome is characterised by the combination of a flaccid iris that billows in response to intraoperative miosis, despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. As IFIS may lead to increased procedural complications during the cataract operation, current or past use of α1-blockers should be made known to the ophthalmic surgeon in advance of the surgery.

Use in hepatic impairment.

See Section 4.3 Contraindications.

Use in renal impairment.

See Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.

Use in the elderly.

In elderly patients, 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 symptoms have completely disappeared. These effects are usually transient, occur at 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 antihypertensive medication). The risk of developing hypotension and related adverse reactions may be greater in elderly patients. Patients should be warned about the possible occurrence of such events.

Paediatric use.

Efficacy of alfuzosin has not been demonstrated in children aged less than 16 years. Therefore alfuzosin is not indicated for use in the paediatric population.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The following combinations are contraindicated:
Use with other α1-blockers, e.g. prazosin, terazosin, doxazosin, tamsulosin.
Concomitant use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir since alfuzosin blood levels are increased (see Section 5.2 Pharmacokinetic Properties, Metabolic interactions).
The following combinations are to be avoided.
Nonselective α1-blockers: phentolamine, labetalol and phenoxybenzamine.
The following combinations are to be taken into account.
Combination with general anaesthetics: the administration to patients treated with alfuzosin may lead to blood pressure instability. Alfuzosin treatment should be stopped 24 hours prior to surgery.
Concomitant use with antihypertensives (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use with nitrates.
Grapefruit juice contains one or more components that inhibit cytochrome CYP3A4. It is not known how combined exposure of any medications metabolised by CYP3A4 (such as modern α1-blockers), herbal remedies (particularly St. John's wort, milk thistle) and grapefruit juice may influence the overall efficacy and unwanted side effects of these medications, therefore, caution should be exercised.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Although α1-adrenoreceptor blockers as a class impair reproductive function in rats, there was no evidence of reproductive organ toxicity when male rats were given alfuzosin at daily oral doses of up to 250 mg/kg/day for 26 weeks, which corresponds to levels of exposure several hundred fold greater than in humans. No impairment of fertility was observed following oral administration to male rats at doses of up to 125 mg/kg/day for 70 days. Oestrous cycling was inhibited in rats and dogs at doses > 5 mg/kg/day, corresponding to levels of systemic exposure (based on AUC of unbound drug) 12 and 18-fold higher than in humans respectively, although this did not result in impaired fertility in rats.
(Category B2)
Drugs which have been taken by only a limited number of pregnant women and women of child-bearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.
Alfuzosin in not intended for use in women. There was no evidence of teratogenicity or embryotoxicity in rats at maternal doses corresponding to systemic exposure levels 1200-fold higher than in humans. Oral treatment with alfuzosin in the rabbit did not show any evidence of foetal toxicity or teratogenicity with maternal doses up to 100 mg/kg/day (250 times the expected human exposure based on BSA).
Gestation was slightly prolonged in rats with maternal dose > 5 mg/kg/day, which corresponds to systemic exposure levels (based on AUC of unbound drug) 12 times higher than human exposure levels, but there were no apparent difficulties with parturition.
Alfuzosin in not intended for use in women. There are no animal or human data indicating whether alfuzosin is excreted in breast milk.

4.7 Effects on Ability to Drive and Use Machines

There are no data available on the use of Xatral SR and its effect on driving vehicles, however, adverse effects such as vertigo, dizziness and asthenia may occur, essentially at the beginning of treatment, and this should be taken into account when driving vehicles and operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials data.

Adverse effects for which an incidence > 1% and greater than placebo was observed during the pivotal clinical study are presented in Table 1. Overall, the incidence of adverse effects in the placebo and alfuzosin 10 mg group was similar (29.2% [45/154] and 32.9% [47/143] respectively). The frequency of study discontinuations due to adverse effects was also comparable between groups (placebo: 3.9% [6/154] and alfuzosin 10 mg daily: 5.6% [8/143]).
The following other adverse events have also been observed with alfuzosin.

Body as a whole.

Common: asthenia.
Uncommon: oedema, flushes, chest pain.

Blood and lymphatic system disorders.

Thrombocytopenia has been reported.

CNS and psychiatric disorders.

Common: faintness/ dizziness, headache.
Uncommon: drowsiness, vertigo.

Cardiovascular disorders.

Uncommon: hypotension, hypotension (postural), syncope, palpitations, tachycardia.
Very rare: angina pectoris in patients with pre-existing coronary artery disease (see Section 4.4 Special Warnings and Precautions for Use).
Atrial fibrillation has been reported.

Eye disorders.

Intraoperative floppy iris syndrome (see Section 4.4 Special Warnings and Precautions for Use) has been reported.

Gastrointestinal disorders.

Common: nausea, abdominal pain/ gastralgia, vomiting.
Uncommon: diarrhoea, dry mouth.

Hepatobiliary disorders.

Hepatocellular injury and cholestatic liver disease have been reported.

Respiratory system disorders.

Uncommon: rhinitis.

Skin and appendages disorders.

Uncommon: rash, pruritis.
Very rare: sweating, urticaria, angioedema.

Reproductive system and breast disorders.

Priapism has been reported.

Note.

Very common: ≥ 1/10 (≥ 10%).
Common: ≥ 1/100 and < 1/10 (≥ 1% and < 10%).
Uncommon: ≥ 1/1000 and < 1/100 (≥ 0.1% and < 1.0%).
Rare: ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%).
Very rare: < 1/10,000 (< 0.01%).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

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.
Alfuzosin in not easily dialyzable because of its high degree of protein binding.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: alpha-adrenoreceptor antagonists, ATC code: G04CA01.

Mechanism of action.

Alfuzosin is a selective antagonist of postsynaptic α1-adrenoreceptors. In vitro pharmacology studies have documented the antagonist properties of alfuzosin for the α1-receptors located in the trigone of the urinary bladder, urethra and prostate. In vivo animal studies have shown that alfuzosin decreases urethral pressures and therefore resistance to the urine flow during micturition.
In benign prostatic hyperplasia (BPH), the development and severity of urinary functional symptoms are related not only to the size of the prostate but also to the tone of the sympathetic nervous system. An α1-adrenergic influence has been shown in smooth muscle fibres of the prostatic stroma. Alfuzosin shows selective tissue distribution in the prostate. There is a hyperplasia of prostate stroma that involves smooth muscle fibres. The lower urinary tract muscle tone is increased by stimulation of the postsynaptic α1-adrenoreceptors. Blockade of these receptors by alfuzosin results in relaxation of smooth muscle fibres. In a study in anaesthetised cats, alfuzosin showed a degree of functional uroselectivity by preferentially decreasing urethral pressure over arterial blood pressure. Evidence of uroselectivity was also seen in a study of conscious male rats. However, in studies of anaesthetised rats and anaesthetised dogs, a selectivity for urethral over vascular smooth muscle was not observed. Pharmacodynamic studies of uroselectivity with alfuzosin have not been conducted in patients with prostate hypertrophy.
α1-Adrenergic blocking agents reduce standing blood pressure and increase heart rate and these effects are maximal after the first intake and at peak plasma concentrations. In clinical studies with alfuzosin, adverse effects related to these effects were infrequent (see Section 4.8 Adverse Effects (Undesirable Effects)).

Clinical trials.

Benign prostatic hyperplasia.

The efficacy of alfuzosin 10 mg daily was assessed in a three month double blind placebo controlled study in patients suffering from benign prostatic hyperplasia: 143 patients received alfuzosin 10 mg daily and 154 patients received placebo.
As shown in Table 2, there was a statistically significant reduction in the overall International Prostate Symptom Score (IPSS) indicating a reduction in symptom severity. This was due to a statistically significant improvement in both the irritative and obstructive subscores. The reduction in Symptom Score was observed at the first postbaseline visit at day 28.
Peak flow rate was also significantly increased, indicating a lessening of obstruction to flow. The effect of Xatral SR was observed as early as day 14 (the first postbaseline assessment). In this study, the assessment of peak flow was made at the end of the dosing interval.

Acute urinary retention.

The use of alfuzosin in the adjuvant therapy of catheterisation after an acute episode of acute urinary retention (AUR) related to BPH and prevention of relapse of AUR have been evaluated in two placebo controlled studies.
In one study (ALFAUR), alfuzosin has been shown to improve the chances of success of spontaneous voiding after a first episode of AUR related to BPH and, during the 6 months after this episode, to postpone the risk of need for surgery. In the first phase of this double blind placebo controlled study, alfuzosin (sustained release formulation) 10 mg/day (N = 241) or placebo (N = 122) was administered for a duration of 3 to 4 days following urethral catheterisation for AUR (starting during the first day of catheterisation to one day after catheter removal). Patients were catheterised for a minimum of 39 hours to a maximum of 70 hours. In the alfuzosin group, 61.9% of patients returned to successful voiding after catheter removal following a first episode of AUR compared with 47.9% of patients in the placebo group (p = 0.012). In men aged 65 years and over, alfuzosin increased the success rate of spontaneous voiding after catheter removal, with 88 successfully voiding (56.1%) in the alfuzosin group, vs 30 (35.7%) in the placebo group (p = 0.003). No benefit was observed in patients in the 50 to 64 year age group, with success in 58 subjects (73.4%) in the alfuzosin group, vs 28 (75.7%) in the placebo group (p = 0.80). Of 204 patients (alfuzosin or placebo) who voided successfully during the first phase of the study, 165 were rerandomised to the second phase of the study, where the need for surgery during the 6 months following the initial AUR episode was assessed. Alfuzosin reduced the risk of need for surgery (emergency surgery due to recurrence of urinary retention or nonemergency surgery) compared to placebo: RR (risk reduction) 61% (p = 0.04), 52% (p = 0.04), 29% (p = 0.2), respectively, at 1, 3 and 6 months treatment with alfuzosin. Survival rates (Kaplan-Meier estimates) for alfuzosin compared to placebo were 93.9% vs 84.3% (p = 0.04) at 1 month, 90.2% vs 78.8% (p = 0.04) at 3 months and 82.5% vs 74.2% (p = 0.2) at 6 months, indicating a statistically significant difference from placebo up to 3 months.
A second study (ALFAURUS) investigated the efficacy of alfuzosin (sustained release formulation) 10 mg/day in the management of AUR secondary to BPH. In this study including 806 patients with a first episode of AUR related to BPH, the success rate at 6 months (successful TWOC [trial without catheter] and no AUR relapse nor need for surgery) was 43.5% for the alfuzosin treated patients and 39.7% for the placebo treated patients.

5.2 Pharmacokinetic Properties

Absorption.

The mean bioavailability relative to the immediate release formulation (2.5 mg three times a day) in middle aged healthy volunteers was 104.4%. The maximum plasma concentration is achieved 9 hours after administration (compared with 1 hour for the immediate release formulation).
Studies have shown that consistent pharmacokinetic profiles are obtained when alfuzosin prolonged release is administered after a meal.

Distribution.

The binding to plasma proteins is about 90%, 68.2% to human serum albumin and 52.5% to human serum α1-glycoprotein.

Metabolism.

The apparent elimination half-life of the prolonged release alfuzosin is 9.1 hours.
Alfuzosin is predominantly metabolised by CYP3A4, with other isoenzymes (e.g. CYP1A2) implicated to a minor extent. Alfuzosin has no significant inhibitory effect on CYP450 isoenzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and is devoid of induction potential on CYP1A, CYP2A6 and CYP3A4 isoenzymes.

Metabolic interactions.

CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin. Ketoconazole is a potent inhibitor of CYP3A4. Repeated 200 mg once 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 (Xatral SR) daily 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, and t1/2Z by 16% (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pharmacokinetics in special populations.

Compared to middle aged healthy 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 pharmacokinetic profile of alfuzosin is not affected by chronic cardiac insufficiency.

Excretion.

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%).

5.3 Preclinical Safety Data

Genotoxicity.

The Ames assay (although inadequate because a single test was conducted) and the mouse lymphoma assay showed that alfuzosin is not mutagenic. Weak evidence of a non dose related clastogenic effect was observed in Chinese Hamster Ovary cells in the absence of S9 fraction. However, this effect was not observed in the same assay in the presence of S9 fraction or in the mouse micronucleus test. Alfuzosin treatment did not induce DNA repair in a human cell line in culture.

Carcinogenicity.

There was no evidence of a drug-related increase in the incidence of tumours in mice and rats following dietary administration of alfuzosin (for 98 and 104 weeks respectively) at doses corresponding to respective levels of systemic exposure (based on AUC of unbound drug) 20-24 and 120-150 times the level of exposure to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethylcellulose, hydrogenated castor oil, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, povidone, silicon dioxide and mannitol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Available in polyvinyl chloride (PVC) / Aluminum foil blister packs and HDPE bottles* of 10, 20, 30 and 60 tablets.
* Presentation not-marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Alfuzosin hydrochloride is a white to off white crystalline powder. It is freely soluble in water.

Chemical structure.


Molecular Weight: 425.9.
Chemical name: (+,-) N-[3-[(4-amino-6,7- dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro- 2-furancarboxamide hydrochloride.

CAS number.

81403-68-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes