Xatral Od

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Document: Xatral OD prolonged-release tablet ENG SmPC change

summary of the product characteristics

1Name of the Medicinal Product

XatralOD 10 mg prolonged‑release tablet

2Qualitative and Quantitative Composition

Each prolonged-release tablet contains Alfuzosin hydrochloride 10 mg

Excipients with known effects:

Hydrogenated castor oil 41.4 mg

For the full list of excipients, see section 6.1.

3Pharmaceutical Form

Prolonged‑release tablet: three‑layer‑tablet, yellow/white/yellow.

4Clinical Particulars

.4.1Therapeutic indications

Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH) including adjunctive therapy with urethral catheterization for acute urinary retention (AUR) related to BPH and management following catheter removal.

.4.2Posology and method of administration

Adults:

BPH: 1 prolonged-release tablet 10 mg daily to be taken after an evening meal.

AUR: One 10 mg tablet daily after a meal to be taken from the first day of catheterization and continued beyond catheter removal unless there is a relapse of acute urinary retention or disease progression.

The prolonged-release tablet should be swallowed whole.

Older people and patients with renal insufficiency:

Based on pharmacokinetic and clinical safety data, older people and patients with renal insufficiency (creatinine clearance 30 ml/min) can be treated with the usual dose. Due to lacking clinical safety data Xatral OD should not be given to patients with severe renal impairment (creatinine clearance <30 ml/min see section 4.4).

Liver insufficiency:

Xatral OD 10 mg is contraindicated in liver insufficiency (see section 4.3).

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 paediatric population.

.4.3Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Conditions with orthostatic hypotension.
Liver insufficiency.
Combination with other alpha-1-blockers.

.4.4Special warnings and precautions for use

Xatral OD 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.

Xatral OD 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). The risk of developing hypotension and related adverse reactions may be greater in older people.

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

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 “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 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.

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.

The excipient hydrogenated castor oil may cause stomach upset and diarrhoea.

.4.5Interaction 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-indicated:

Alpha-1-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)

Ketoconazole: Repeated 200 mg daily dosing of ketoconazole, for seven days resulted in a 2.1 fold increase in C_maxand a 2.5 fold increase in exposure of alfuzosin 10 mg OD when administered under fed conditions. Other parameters such as t_maxand t_1/2were not modified.

The increase in alfuzosin C_maxand AUC_(last) following repeated 400 mg daily administration of ketoconazole was 2.3-fold, and 3.2-fold, respectively (see section5.2).

.4.6Fertility, pregnancy and lactation

Not relevant.

.4.7Effects on ability to drive and use machines

There are no data available on reduced reaction ability.

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

.4.8Undesirable effects

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

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)

Blood and lymphatic system disorders
Not known	Neutropenia, thrombocytopenia
Cardiac disorders
Uncommon	Syncope (initially above all with too high a dose or if treatment is started again after a short interruption of therapy), postural hypotension (see section 4.4) (initially above all with too high a dose or if treatment is started again after a short interruption of therapy), tachycardia
Very rare	Angina pectoris predominantly in patients with pre-existing coronary heart disease (see section 4.4)
Not known	Atrial fibrillation
Nervous system disorders
Common	Dizziness, headache
Uncommon	Vertigo, drowsiness
Eye disorders
Not known	Intraoperative floppy iris syndrome (see section 4.4)
Respiratory, thoracic and mediastinal disorders
Uncommon	Rhinitis
Gastrointestinal disorders
Common	Abdominal pain, nausea, dyspepsia
Uncommon	Vomiting, diarrhoea, dryness of the mouth
Skin and subcutaneous tissue disorders
Uncommon	Rash (urticaria, exanthema), pruritus
Very rare	Angioedema
General disorders and administration site conditions
Common	Asthenia
Uncommon	Chest pain, oedema, hot flushes
Hepatobiliary disorders
Not known	Hepatocellular injury, cholestatic liver disease
Reproductive system and breast disorders
Not known	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 national reporting system listed in [To be completednationally].

.4.9Overdose

In case of overdose, conventional treatment such as addition of fluids and vasopressor drugs should take place in a hospital. The patient should be kept in the supine position.

In case of significant hypotension, the appropriate corrective treatment may be a vasoconstrictor that acts directly on vascular muscle fibers.

Alfuzosin is not easily dialysable because of its high degree of protein binding. Active charcoal should be administered following possible gastric lavage.

5Pharmacological Properties

.5.1Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in benign prostatic hypertrophy. ATC code: G04C A01

Alfuzosin,which is a racemate, isan oral quinazoline derivative, which selectively blocks post synaptic alpha‑1‑receptors. In vitrostudies have confirmed the selectivity of the substance on alpha‑1‑receptors in the trigone of the urine bladder, urethra and prostate. The clinical symptoms in benign prostatic hyperplasia are not only related to the size of the prostate, but also to the sympathomimetic nerve impulse, which by stimulating the post synaptic alpha receptors increase the tension of the smooth muscles of the lower urinary tract. During treatment with alfuzosin, smooth muscles are relaxed and thus urine flow is improved.

Clinical evidence of uroselectivity has been demonstrated by clinical efficacy and good safety profile in men treated with alfuzosin, including older people and hypertensive men.

In man, alfuzosin improves voiding by reducing urethral tone and bladder outlet resistance, and facilitates bladder emptying.

In placebo controlled studies in BPH patients, alfuzosin:

significantly increased peak flow rate (Q_max) in patients with Q_max <15 ml/s by a mean 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.

The efficacy on peak flow rate is observed up to 24 hours after intake.

These urodynamic effects lead to an improvement of lower urinary tract symptoms (LUTS) i.e. filling (irritative) as well as voiding (obstructive) symptoms which was clearly demonstrated.

A lower frequency of acute urinary retention (AUR) was observed in alfuzosin treated patients than in untreated patients. In addition, alfuzosin significantly increased the success rate of spontaneous voiding after catheter removal in men with a first episode of AUR related to BPH and, in comparison with placebo, reduced the need of surgery for AUR relapse for up to 3 to 6 months.

Paediatric population

Xatral OD 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.

.5.2Pharmacokinetic properties

Alfuzosin:

Alfuzosin shows linear kinetics in the therapeutic dosage area. Bioavailability is 64%, when administered as an immediate release formulation (2.5 mg). Maximal plasma concentration is reached within 0.5‑6 hours after administered dose. The kinetic profile is characterised by large inter‑individual fluctuations (sevenfold) in plasma concentrations. Plasma half-life is approximately 5 hours (1‑10 hours). The pharmacokinetic profile is not altered when alfuzosin is administered with food.

Plasma protein binding is about 90%. Alfuzosin is eliminated by metabolism, renal excretion and probably also biliar excretion. After extensive metabolism by the liver the majority of the metabolites are recovered in faeces (75% to 91%). CYP3A4 is the main hepatic enzyme isoform involved in the metabolism of alfuzosin (see section 4.5). None of the metabolites has any pharmacological activity.

Volume of distribution and clearance is increased in reduced renal function, possibly due to decreased protein binding capacity. Half‑life is however unchanged. In patients with severe hepatic insufficiency, the elimination half‑life is prolonged. A two‑fold increased in C_maxand three‑fold increase in AUC is observed. Bioavailability is increased in comparison to that in healthy volunteers.

Older peoplehave higher bioavailability, which leads to higher maximum plasma concentrations but unchanged half‑life.

Prolonged-release tablets 10 mg:

The mean value of the relative bioavailability is 104.4% versus the immediate release formulation (2.5 mg tid) in middle aged healthy volunteers. The maximal plasma concentration is being achieved 9 hours after the administration compared to 1.0 hour for the immediate release formulation.

The apparent elimination half-life is 9.1 hours.

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

Under fed conditions, mean C_maxand C_troughvalues are 13.6 (SD=5.6) and 3.2 (SD=1.6) ng/ml respectively. Mean AUC_0‑24is 194 (SD=75) ng ^. h/ml.

Compared to healthy middle aged volunteers, the pharmacokinetic parameters (C_maxand AUC) are not increased in older people.

Compared to subjects with normal renal function, mean C_maxand 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 for patients with creatinine clearance >30 ml/min.

.5.3Preclinical safety data

Non-clinical data reveal no special hazard for humans.

6Pharmaceutical Particulars

.6.1List of excipients

ethylcellulose

hydrogenated castor oil

hypromellose

yellow iron oxide (E 172)

magnesium stearate

microcrystalline cellulose

silica colloidal hydrated

mannitol

povidone

.6.2Incompatibilities

Not applicable.

.6.3Shelf life

3 years

.6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

.6.5Nature and contents of container

Blister (aluminium/PVC): 10, 30, 90

Bottle (polyethylene): 100

Not all pack sizes may be marketed.

.6.6Special precautions for disposal

No special requirements.

7Marketing Authorisation Holder

[To be completed nationally]

8Marketing authorisation number(s)