SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zochek 10 mg prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 10 mg alfuzosin hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

White to off-white round (diameter 8.1 mm), biconvex, film-coated tablets debossed with ‘X’ on one side and ‘47’ on other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

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 patients (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.

Contraindications

•    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

4.4 Special warnings and precautions for use

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. 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).

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

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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)

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 tmax and t1/2 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.

4.6 Fertility, pregnancy and lactation

In view of the area of indication this section is not applicable.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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)._

	Frequency
	Common	Uncommon	Very rare	Not Known
Blood and lymphatic system disorders				Neutropenia, thrombocytopenia
Cardiac disorders		Tachycardia	Angina pectoris in patients with pre-existing coronary	Atrial fibrillation

			artery disease (see section 4.4)
Vascular disorders		Hypotension (postural), flushing
Nervous system disorders	Dizziness, headache	Syncope, Vertigo
Eye disorders				Intraoperative floppy iris syndrome
Respiratory, thoracic and mediastinal disorders		Rhinitis
Gastrointestinal isorders	Nausea, abdominal pain	Diarrhoea		Vomiting
Skin and subcutaneous tissue disorders		Rash, pruritus	Urticaria, angioedema
General disorders and administration site conditions	Asthenia	Oedema, chest pain
Hepatobiliary disorders				Hepatocellular injury, cholestatic liver disease
Reproductive system and breast disorders				Priapism

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.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

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 Qmax<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.

5.2 Pharmacokinetic properties

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 (AUCt) 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 halflife, 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 patients

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%) remains unchanged.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Zochek tablets are available in PA/Aluminium/PVC/Aluminium blister packs and white opaque round HDPE bottles containing silica gel sachets. A cotton coil is used to fill the void in the HDPE bottle.

Package sizes:

Blister pack: 30, 50 & 100 tablets HDPE bottle pack: 30 & 1000 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Milpharm Limited

Ares Block, Odyssey Business Park

West End Road

Ruislip HA4 6QD

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0405

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/04/2014

10    DATE OF REVISION OF THE TEXT

14/04/2014