Zochek 10 mg Prolonged Release Tablets

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

Oral Use

The prolonged-release tablet should be taken whole with sufficient amount of fluid (e.g. a glass of water). The prolonged-release tablets must not be crushed, chewed or divided (see section 4.4).

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

Adults:

The recommended dose is one 10 mg prolonged-release tablet daily.

Elderly (over the age of 65 years)

The recommended dose is the same as that for adults. Pharmacokinetic and clinical safety studies have shown that dose adjustment is not necessary in the case of elderly patients.

Impaired renal function

Mild to moderate renal insufficiency (creatinine clearance > 30 ml/min): Dose reduction is usually not necessary (see section 5.2).

Severe renal insufficiency

Alfuzosin 10 mg 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).

Hepatic insufficiency:

Alfuzosin, given as 10 mg prolonged-release tablets are contraindicated in patients with hepatic insufficiency. Preparations containing a low dose of alfuzosin hydrochloride might be used in patients with mild to moderate hepatic insufficiency as instructed in the corresponding product information.

Paediatric population:

Efficacy of alfuzosin has not been demonstrated on children aged 2 to 16 years (see section 5.1). Therefore, alfuzosin is not indicated for use in paediatric population.

• Hypersensitivity to the alfuzosin hydrochloride, other quinazolines (e.g. terazosine, doxazosine) or to any of the excipients listed in section 6.1

• Previous history of orthostatic hypotension

• Liver insufficiency

• Combination with other alpha 1- blockers

Zochek 10 mg tablets should not be given to patients with severe renal impairment (creatinine clearance < 30 ml/min) in view of the lack of clinical safety data in this group of patients.

Alfuzosin should be given with caution to patients who are on antihypertensive medication or nitrates.

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

These effects are usually transient, occur in 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 anti-hypertensive medication). The risk of developing hypotension and related adverse reactions may be greater in elderly patients.

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

In coronary patients, the specific treatment for coronary insufficiency should be continued. If angina pectoris reappears or worsens, alfuzosin should be discontinued.

As with all alpha-1-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

Concomitant use of alfuzosin and potent CYP3A4 inhibitors (such as itraconazole, ketoconazole, protease inhibitors, clarithromycin, telithromycin and nefazodone) should be avoided (see section 4.5). Alfuzosin should not be used concomitantly with CYP3A4 inhibitors that are known to increase the QTc interval (e.g. itraconazole and clarithromycin) and a temporary interruption of alfuzosin treatment is recommended if treatment with such medicinal products is initiated.

The 'Interoperative 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 opthalmic surgeon in advance of surgery.

Alfuzosin, like other alpha adrenergic antagonist, has been associated with priapism (persistent painful penile erection unrelated to sexual activity; see section 4.8). Because this condition can lead to permanent impotence if not properly treated, patients should be advised to seek immediate assistance in the event of an erection that persists longer than 4 hours.

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.

No pharmacodynamic or pharmacokinetic interactions have been observed in studies with healthy volunteers between alfuzosin and the following drugs:

warfarin, digoxin, hydrochlorothiazide and atenolol.

Administration of general anaesthetics to a patient treated with alfuzosin may lead to blood pressure instability.

Combinations contra-indiacted

- Alpha-1 receptor blockers (see section 4.3)

Increased hypotensive effect. Risk of severe orthostatic hypotension.

Concomitant use not recommended:

- Potent CYP3A4 inhibitors such as itraconazole, ketoconazole, protease inhibitors, clarithromycin, telithromycin and nefazodone since alfuzosin blood levels may be increased (see section 4.4)

Combinations to be taken into account

- Antihypertensive drugs (see section 4.4)

- Nitrates (see section 4.4)

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 OD 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 section5.2).

See also section 4.4.

As Alfuzosin is not used in women, this section does not apply.

There are no data available on the effect on driving vehicles.

Adverse reactions such as dizziness and asthenia may occur essentially at the beginning of treatment. This has to be taken into consideration when driving vehicles and operating machines.

Tabulated list of adverse reactions

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.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

In case of overdosage, the patient should be hospitalized, 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 highly protein-bound, therefore, dialysis may not be of benefit.

Pharmacotherapeutic category: alpha-adrenoreceptor antagonists. ATC code: G04C A01 Alfuzosin

Mechanism of action

Alfuzosin, a racemic compound, is an orally active quinazoline derivative that selectively blocks post-synaptic alpha-l-receptors. In vitro studies have shown that the substance acts selectively on alpha-1-receptors in the trigone of the urine bladder, the urethra and the prostate gland. The clinical symptoms of benign prostate hyperplasia are not only related to the size of the prostate but also to the sympathicomimetic nerve impulses which through stimulation of the postsynaptic alpha-receptors increase the tension of the smooth muscles of the lower urinary tract. Through treatment with alfuzosin the smooth muscles relax as a result of which the urine flow improves.

The clinical evidence of the selective effect on the urinary tract is shown by the clinical efficacy and the good safety profile in men treated with alfuzosin, including elderly patients and patients with hypertension. Alfuzosin can result in moderate antihypertensive effects.

In men, alfuzosin improves the voiding of water by reducing urethral muscle tone and bladder outlet resistance, thereby facilitating bladder emptying.

In patients treated with alfuzosin a lower frequency of acute urine retention was observed than in untreated patients.

In placebo-controlled studies in patients with benign prostate hyperplasia alfuzosin:

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

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

- a significantly reduced the residual urine volume.

These urodynamic effects result in an improvement in lower urinary tract symptoms (LUTS), i.e. symptoms relating to retention (irritating) and urine discharge (obstructive) which is clearly demonstrated.

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.

Alfuzosin has linear pharmacokinetics in the therapeutic dosage range. The kinetic profile is characterised by large inter-individual fluctuations in the plasma concentration. Absorption is increased when the medication is administered after a meal.

Absorption

After the first dose (following a meal) the mean maximum plasma concentration was 7.72 ng/ml and the AUC_inf 127 ng x h/ml (after a meal) and the t_max was 6.69 hours (after a meal).

In steady state conditions (after a meal) the mean AUC over the dosage interval (AUC) was 145 ng x h/ml, the mean C_max 10.6 ng/ml and C_min was 3.23 ng/ml.

Distribution

Plasma protein binding is approx. 90%. The distribution volume of alfuzosin in healthy test subjects is 2.5 l/kg. It has been shown that the substance is distributed more in the prostate than in the plasma.

Elimination

The apparent elimination half-life is approximately 8 hours. Alfuzosin is largely metabolised in the liver (various routes), the metabolites are eliminated by the kidneys and probably also via the bile, 75-91% of an oral dose is eliminated in the faeces, 35% in unmodified form and the rest as metabolites, which indicates that some excretion via the bile takes place. Around 10% of the dose is eliminated in unmodified form in the urine. None of the metabolites are pharmacologically active.

Renal or hepatic impairment

The volume of distribution and clearance increases with reduced renal function, possibly owing to a decreased degree of protein binding. The half-life, however, is unchanged. This change in the pharmacokinetic profile is not considered clinically relevant. Therefore, this does not necessitate a dosing adjustment in patients with mild to moderate renal insufficiency (see sections 4.2 and 4.4).

The half-life is prolonged in patients with severe hepatic insufficiency. The peak plasma concentration is doubled and the bioavailability increases in relation to that in young, healthy volunteers. Alfuzosin 10 mg prolonged release tablets are contraindicated in hepatic insufficiency (see section 4.3).

Elderly

Compared to healthy middle-aged volunteers, the peak plasma concentration (C_max) and bioavailability (AUC) are not increased in elderly patients. The elimination half-life (t_½ ) remains unchanged.

Pre-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity, carcinogenic potential or reproductive toxicity for males. In vitro, alfuzosin prolonged the action potential duration and QT interval duration at a clinically relevant concentration.

Tablet core:

Hypromellose (E464)

Hydrogenated vegetable oil

Povidone (K-30) (E1201)

Calcium hydrogen phosphate anhydrous

Carbomer

Silica colloidal anhydrous (E551)

Magnesium stearate (E572)

Film- coating:

Hypromellose (E464)

Propylene glycol

Titanium dioxide (E171)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

Zochek tablets are available in clear PVC/PVdC-Aluminium blister packs and white opaque round HDPE bottles containing silica gel.

Package sizes:

Blister pack: 30, 50, 90 & 100 tablets

HDPE bottle pack: 30, 500 & 1000 tablets

Not all pack sizes may be marketed.

No special requirements