Taurazil XL 10 mg Tablets

Each tablet contains 10 mg alfuzosin hydrochloride

Excipients with known effects:

Each tablet contains 7.6mg lactose as (lactose monohydrate).

For the full list of excipients, see section 6.1.

Prolonged-release tablet

White, round, bevelled-edge, uncoated tablets.

Treatment of moderate to severe functional symptoms of benign prostatic hyperplasia (BPH).

Posology

Adults

BPH: One 10 mg prolonged-release tablet once daily. The first dose should be taken at bedtime. The tablet should be taken immediately after the same meal each day.

Elderly (over 65 years)

Pharmacokinetic and clinical safety data demonstrate that no dose reduction is necessary for elderly patients. A lower initial dose may, however, be considered for patients with increased risk of undesirable effects.

Paediatric population:

The safety and efficacy of alfuzosin have not been demonstrated in children aged 2 to 16 years (see section 5.1). Therefore, alfuzosin is not indicated for use in paediatric population.

Patients with reduced renal function

Mild to moderate renal insufficiency

If a lower dose is not sufficient, therapy can be adjusted to one 10 mg prolonged- release tablet daily according to clinical response. The first dose should be taken at bedtime.

Severe renal insufficiency

Taurazil XL 10 mg prolonged-release tablets should not be given to patients with severely impaired renal function (creatinine clearance < 30 ml/min) as there are no clinical safety data available for this patient group (see section 4.4).

Patients with hepatic insufficiency

Taurazil XL given as 10mg prolonged release tablets is contraindicated in patients with hepatic insufficiency. An immediate-release preparation containing a low dose alfuzosin hydrochloride may be used in patients with mild to moderate hepatic insufficiency. See the corresponding product information for dosing instructions.

Method of administration

For oral use.

The prolonged-release tablet should be swallowed whole with a sufficient amount of fluid (see section 4.4).

- Hypersensitivity to the active substance, other quinazolines (e.g. terazosin, doxazosin) or to any of the excipients listed in section 6.1.

- Conditions with orthostatic hypotension.

- Liver insufficiency.

- Combination with other alpha₁-receptor blockers.

Patients with severe renal impairment

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 (see section 4.2).

Risk of hypotension

Taurazil XL should be given with caution to patients who are on antihypertensive medication or nitrates. Blood pressure should be monitored regularly, especially at the beginning of treatment.

In coronary patients, the specific treatment for coronary insufficiency should be continued, taking into account that the concomitant administration of nitrates and alfuzosin may increase the risk of occurrence of hypotension. If angina pectoris reappears or worsens, alfuzosin should be discontinued.

In some subjects postural hypotension may develop, with or without symptoms (dizziness, fatigue asthenia, sweating) within a few hours following administration. In such cases, the patient should lie down until the symptoms have totally disappeared.

These effects are 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 disease and/or concomitant treatment with anti-hypertensive medication). The risk of developing hypotension and related adverse reactions may be greater in older people. Patients should be warned about the possibility of these effects.

There is a risk of cerebral ischaemic disorders in patients with symptomatic or asymptomatic pre-existing cerebral circulatory disturbances, due to the fact that hypotension may develop following alfuzosin administration (see section 4.8).

Care should be taken when alfuzosin is administered to patients who have had a pronounced hypotensive response to another alpha₁-receptor blocker.

Previous history of hypersensitivity to other alpha₁-receptot blockers

Treatment should be initiated gradually in patients with hypersensitivity to other alpha₁-receptor blockers.

Cardiac failure

As with all alpha₁-receptor blockers, alfuzosin should be used with caution in patients with acute cardiac failure.

QTc prolongation

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.

Intraoperative Floppy Iris Syndrome

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 alpha₁-receptor blockers and the possibility of a class effect cannot be excluded. . As IFIS may lead to increased procedural complications during the operation, the surgeon should be informed of current or past alpha₁-receptor blocker use and prepare for possible modifications to their surgical technique.

Tablet administration

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.

Lactose

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

Combinations contra-indicated:

• Alpha₁-receptor blockers (see section 4.3).

Combinations to be taken into account:

• Antihypertensive drugs (see section 4.4).

• Nitrates (see Section 4.4 )

• Potent CYP3A4 inhibitors such as itraconazole, ketoconazole, protease inhibitors, clarithromycin, telithromycin and nefazodone since alfuzosin blood levels are increased (see section 5.2).

• Patients being treated with alfuzosin must be haemodynamically stable before treatment with a phosphodiesterase-5 inhibitor (sildenafil, tadalafil, vardenafil) is initiated.

Ketoconazole

Repeated 200 mg daily dosing of ketoconazole, for seven days resulted in a 2.1-fold increase in C_max and a 2.5-fold increase in exposure of alfuzosin 10 mg prolonged-release tablets when administered under fed conditions. Other parameters such as t_max and t_1/2 were not modified.

The increase in alfuzosin C_max and AUC_(last) following repeated 400 mg daily administration of ketoconazole was 2.3-fold and 3.2-fold respectively (see section 5.2).

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

No pharmacodynamic or pharmacokinetic interactions have been observed in studies with healthy volunteers between alfuzosin and the following active substances: warfarin, digoxin, hydrochlorothiazide and atenolol.

Pregnancy/Breast-feeding

Due to the indication area this section is not applicable.

Fertility

No data are available

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 consideration when driving vehicles and operating machines.

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)

The most commonly reported event is dizziness, which occurs in approximately 5% of treated patients.

* at start of treatment, with too high a dose or after short interruption of treatment

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Symptoms

Hypotension, reflex tachycardia

Management

In case of overdose, 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.

Gastric lavage and/or administration of medicinal charcoal should be considered. Taurazil XL is highly protein-bound, therefore, dialysis may not be of benefit

Pharmacotherapeutic group: Drugs used in benign prostatic hypertrophy, alpha- adrenoreceptor antagonists

ATC code: G 04 CA 01

Mechanism of action

Alfuzosin, which is a racemate, is an orally acting quinazoline derivative which selectively blocks post-synaptic alpha₁-receptors.

Pharmacodynamic effects

In vitro studies have confirmed the selectivity of alfuzosin for alpha₁-adrenoreceptors located in the prostate, the trigonum vesicae and the prostatic urethra.

Clinical efficacy and Safety

Benign Prostatic Hypertrophy (BPH)

The clinical symptoms in BPH are not only related to the size of the prostate, but also to sympathomimetic nerve impulses, which by stimulating the post-synaptic alpha receptors increase the tension of the smooth muscle of the lower urinary tract. Treatment with alfuzosin relaxes this smooth muscle, thus improving the urinary flow.

Clinical evidence of uroselectivity has been demonstrated by clinical efficacy and a good safety profile in men treated with alfuzosin, including the elderly and patients with hypertension.

However, alfuzosin may cause moderate anti-hypertensive effects.

In humans, alfuzosin improves the voiding of water by reducing the urethral muscle tone, with reduction in the resistance to outflow from the bladder, making it easier to empty the bladder.

In placebo-controlled studies of BPH patients, alfuzosin has:

- significantly increased maximum urinary flow (Q_max) in patients with Q_max <15 ml/s by an average of 30%. This improvement was observed from the first dose,

- significantly reduced the detrusor pressure and increased the volume producing a strong desire to void,

- significantly reduced the residual urine volume.

These urodynamic effects lead to an improvement of Lower Urinary Tract Symptoms (LUTS), i.e. filling (irritative) as well as voiding (obstructive) symptoms, which has been clearly demonstrated.

Acute urinary retention (AUR) related to BPH

Alfuzosin has been shown to increase the chances of successful spontaneous urination at first episode of acute urinary retention (AUR) related to BPH and in the following six months after this episode, reducing the requirement for surgery.

In a double-blind placebo-controlled study including 357 patients, alfuzosin 10 mg daily increased the success rate of spontaneous urination after catheter removal in men over 65 years.

88 patients (56.1%) in alfuzosin group had successful urination, while 30 patients (35.7%) in the placebo treatment had successful urination (p = 0.003).

165 patients who achieved successful urination during the first phase were included in the second phase and were re-examined: alfuzosin reduced the risk of surgery (both emergency surgery due to recurrence of AUR or as non-emergency) compared to placebo with a risk reduction of respectively 61%, 52%, and 29% at 1, 3 and 6 months of treatment with alfuzosin.

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.

Absorption

The maximal plasma concentration is achieved 9 hours after administration.

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

After the first dose (fed) the mean maximum plasma concentration was 7.72 ng/ml,

AUCinf was 127 ng x h/ml (fed), and tmax was 6.69 h (fed). Under steady state conditions (fed) the mean AUC over the dosing interval (AUC) was 194 (SD = 75) ng x h/ml, mean Cmax was 13.6 (SD = 5.6) ng/ml and Cmin was 3.1 (SD = 1.6) ng/ml.

Distribution

The binding rate to plasma protein is approx. 90%. Alfuzosin's distribution volume is 2.5 l/kg in healthy volunteers. It has been shown to preferentially distribute in the prostate in comparison to plasma.

Biotransformation

Alfuzosin is extensively metabolised in the liver (through various routes). None of the metabolites are pharmacologically active.

Metabolic interactions: CYP3A4 isoform is the principal hepatic enzyme involved in the metabolism of alfuzosin (see section 4.5).

Elimination

The apparent elimination half-life is approx. 9.1 hours.

Alfuzosin metabolites are eliminated via renal excretion and probably also via biliary excretion.

Of an oral dose, 75-91% is excreted in the faeces, 35% in unmodified form and the rest as metabolites, which indicates some degree of biliary excretion. About 10% of the dose is excreted in the urine in its unmodified form.

Linearity/non-linearity

Alfuzosin has linear pharmacokinetic properties within the therapeutic dose range.

Renal or hepatic impairment

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 with creatinine clearance >30ml/min.

In patients with severe hepatic insufficiency the half-life is prolonged. The peak plasma concentration is doubled and the bioavailability increases in relation to that in young, healthy volunteers.

Elderly patients

C_max and AUC are not increased in elderly patients compared to healthy middle-aged volunteers.

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, or reproductive toxicity.

Lactose monohydrate

Hypromellose

Povidone K25

Magnesium stearate

Not applicable

4 years

Do not store above 30°C.

PVC/PVDC-aluminium blister.

10, 20, 30, 30x1, 50, 60, 60x1, 90, 100 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

Generics [UK] Limited t/a Mylan,

Station Close,

Potters Bar,

Hertfordshire,

EN6 1TL

United Kingdom

PL 04569/0774

05/09/2010

July 2016