SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bundisarin XL 10mg prolonged release tablets

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 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, biconvex, film-coated tablets debossed with ‘X’ on one side and ‘47’ on the 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

Posology

Adults:

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

Older people (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 older people.

Patients with renal impairment

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

Patients with severe renal impairment

Bundisarin XL 10mg 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 impairment:

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 in children aged 2 to 16 years (see section 5.1).

Therefore Alfuzosin is not indicated for use in the paediatric population.

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.

4.3    Contraindications

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

•    Previous history of orthostatic hypotension

•    Hepatic insufficiency

•    Combination with other alpha-1 receptor blockers

4.4    Special warnings and precautions for use

•    The patient should be examined before commencement of therapy with alfuzosin to exclude the presence of other conditions that can produce similar symptoms to those of BPH.

•    Bundisarin XL 10mg prolonged release tablets should not be administered to patients with a severe renal function disorder (creatinine clearance < 30 ml/min) as no clinical safety data are available for this group of patients.

•    Care must be taken if Bundisarin XL 10mg prolonged release tablets are administered to patients who are being treated with antihypertensives. Blood pressure must be regularly monitored, particularly at the start of the treatment.

•    In some patients orthostatic hypotension can occur within a few hours of administration, with or without symptoms (dizziness, tiredness, sweating). This effect is of a temporary nature, occurs at the start of the treatment and usually does not require the treatment to be stopped. The patient should be warned that these symptoms may possibly occur. In such cases the patient should rest lying down until the symptoms have completely disappeared.

•    Pronounced drop in blood pressure has been reported in post-marketing surveillance in patient 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 older people (see section 4.8). Caution should be exercised when prescribing Bundisarin to older people. The patient should be warned of the possible occurrence of such events.

•    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 ophthalmic surgeon in advance of surgery.

•    Caution is urged if alfuzosin is administered to patients who have reacted to other alpha-1-receptor blockers with severe hypotension.

•    The treatment should be started gradually in patients who are sensitive to other alpha-l-receptor blockers.

•    Like all alpha-1-receptor blockers alfuzosin should be used with caution in patients with acute cardiac failure.

•    In the case of cardiac patients the treatment of coronary insufficiency should be continued, taking into account the fact that concomitant administration of nitrates and alfuzosin can increase the risk of hypotension occurring. If angina pectoris recurs the treatment with alfuzosin should be stopped.

•    Patients should be instructed to take the tablet whole. Other methods of administration such as crushing, pulverising or chewing the tablets must be avoided. Incorrect administration can lead to undesirable release and absorption of the active substance with the risk of early side effects.

•    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.

4.5 Interaction with other medicinal products and other forms of interaction

Contra-indicated combinations (see section 4.3)

-    Alpha-1 receptor blocking agents

Increased hypotensive effect. Risk of severe orthostatic hypotension. Combinations not recommended

-    Potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin)

Increase the plasma concentration of alfuzosin and increase the risk of undesirable effects.

Combinations to be taken into account (see section 4.4)

-    Antihypertensive drugs

antihypertensive effect and risk of increased hypotension (cumulative effect).

-    Nitrate preparations.

Administration of an anaesthetic to a patient being treated with alfuzosin may lead to profound hypotension. It is recommended that the tablets be withdrawn 24 hours before surgery.

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

No studies have been carried out into the effect on the ability to drive and use machines.

Undesirable effects such as vertigo, dizziness and asthenia can occur particularly at the start of the treatment. This should be taken into account when driving vehicles or using machines.

4.8 Undesirable effects

The adverse reactions considered at least possibly related to treatment are listed below by body system organ class and absolute frequency.

Frequencies are defined as 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
Nervous system disorders	Dizziness, headache	Somnolence, Vertigo, Malaise, Syncope
Eye disorders		Vision abnormal		Intraoperative Floppy Iris Syndrome (see section 4.4)
Cardiac disorders		Tachycardia, palpitations	Aggravation or recurrence of angina pectoris in patients with pre-existing coronary artery disease (see section	Atrial fibrillation

			4.4)
Vascular disorders		Orthostatic hypotension, flushing
Blood and lymphatic system disorders				Neutropenia
Respiratory, thoracic and mediastinal disorders		Rhinitis
Gastrointestinal disorders	Nausea, abdominal pain	Vomiting, diarrhoea, dry mouth
Hepatobiliary disorders			Hepatotoxicity	Hepatocellular injury, cholestatic liver disease
Skin and subcutaneous tissue disorders		Skin rashes, pruritus	Urticaria, Angioneurotic oedema
Reproductive system and breast disorders				Priapism
Renal and urinary disorders		Urine incontinence
General disorders and administration site conditions	Asthenia	Oedema, chest pains(see section 4.4)

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 overdose, the patient should be admitted to hospital and given normal support therapy for hypotension. The appropriate antidote is a vasoconstrictor that acts directly on the smooth muscle in the blood vessels such as noradrenaline.

Gastric flushing and/or the administration of medicinal charcoal should be considered. Alfuzosin is not easily dialysed due to the strong degree of protein binding.

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 postsynaptic 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 older people 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,

-    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.

Alfuzosin may cause moderate antihypertensive effects.

Paediatric Population

Alfuzosin is not indicated for use in the paediatric population (see section 4.2). Efficacy of alfuzosin hydrochloride was not demonstrate in the two studies conducted in 197 patients 2 to 16 years of age with elevated detrusor leak point pressure (LLP>40cm H₂0) 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. Bundisarin XL 10 mg prolonged release tablets are contraindicated in hepatic insufficiency (see section 4.3).

Older people

Compared to healthy middle-aged volunteers, the peak plasma concentration (Cmax) and bioavailability (AUC) are not increased in older people. The elimination half-life (t²) 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 toxicity to reproduction 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 (E1201)

Calcium hydrogen phosphate (E341) Carbomer

Silica colloidal anhydrous (E551) Magnesium stearate (E470b)

Tablet coat:

Hypromellose (E464)

Propylene glycol (E1520)

Titanium dioxide (E 171)

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

Bundisarin XL 10mg prolonged release tablets are available in Alu / Alu blister pack, and HDPE tablet container with a silica gel desiccant.

Pack size:

Alu / Alu blister pack: 10, 14, 20, 28, 30, 50, 56, 60, 84, 90 and 100 tablets HDPE container pack: 30 and 1000 tablets Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Amneal Pharma Europe Limited 70 Sir John Rogerson’s Quay,

Dublin 2,

Ireland.

MARKETING AUTHORISATION NUMBER(S)

PL 42357/0005

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/02/2011

DATE OF REVISION OF THE TEXT

10/10/2014