Alfuzosin Orion

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summary of product characteristics

1Name of the Medicinal Product

Alfuzosin Orion 2.5 mg film-coated tablets

2Qualitative and Quantitative Composition

Each tablet contains 2.5 mg of alfuzosin hydrochloride.

Excipients with known effects: 61.1 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3Pharmaceutical Form

Film-coated tablet

White to off-white round, biconvex, film-coated tablets debossed with ‘X’ on one side and ‘31’ on other side.Diameter of the tablet is 6.1 mm.

4Clinical Particulars

.4.1Therapeutic indications

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

.4.2Posology and method of administration

The first dose should be given just before bedtime.

Posology

Adults

The usual dose is 1 tablet three times daily. The dose may be increased to a maximum of 1 tablet four times daily (10 mg) depending on the clinical response.

Elderly and treated hypertensive patients

As a routine precaution when prescribing alfuzosin to elderly patients (aged over 65 years) and the treated hypertensive patient, the initial dose should be 1 tablet in the morning and 1 tablet in the evening.

Renal insufficiency

In patients with renal insufficiency, as a precaution, it is recommended that the dosing be started at 1 tablet 2.5mg twice daily adjusted according to clinical response.

Hepatic insufficiency

In patients with mild to moderate hepatic insufficiency, it is recommended that therapy should commence with a single dose of 2.5 mg tablets daily to be increased to 2.5 mg tablets twice daily according to clinical response.

Severe hepatic 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 excipientslisted in section 6.1.

Conditions with orthostatic hypotension.

Severe hepatic insufficiency.

Combination with other alpha-1-receptor blockers.

.4.4Special warnings and precautions for use

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

In some subjects postural hypotension may develop, with or without symptom (dizziness, fatigue, sweating) within a few hours following administration. These effects are 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.

There is a risk of cerebral ischemic 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 alpha-1-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 “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.

Alfuzosin Orion 2.5 mg film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose‑galactose malabsorption should not take this medicine.

.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 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 section 5.2).

.4.6Fertility, pregnancy and lactation

Due to the type of indication this section is not applicable.

.4.7Effects on ability to drive and use machines

There are no data available on reduced reaction ability.

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.

.4.8Undesirable 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).

Tabulated list of adverse reactions

MedDRA system organ class	Common ≥1/100 to <1/10	Uncommon ≥1/1,000 to <1/100	Very rare <1/10,000	Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders				Neutropenia, thrombocytopenia
Nervous system disorders	Vertigo, dizziness, malaise, headache	Drowsiness		Cerebral ischemic disorders in patients with underlying cerebrovascular disturbances*
Eye disorders		Vision abnormal		Intraoperative floppy iris syndrome*
Cardiac disorders	Postural hypotension (initially or if treatment is started again after a short interruption of therapy)*	Syncope (initially or if treatment is started again after a short interruption of therapy), tachycardia, palpitations	Angina pectoris predominantly in patients with pre-existing coronary heart disease*	Atrial fibrillation
Respiratory, thoracic and mediastinal disorders		Rhinitis
Gastrointestinal disorders	Abdominal pain , diarrhoea, nausea, dryness of the mouth	Vomiting, dyspepsia
Hepatobiliary disorders				Hepatocellurar injury, cholestatic liver disease
Skin and subcutaneous tissue disorders		Rash (urticaria, exanthema), pruritus	Angioedema
Renal and urinary disorders		Urinary incontinence
Reproductive system and breast disorders				Priapism
General disorders and administration site conditions	Asthenia	Hot flushes, oedema, chest pain

* For more information, 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 national reporting system listed in Appendix V.

.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: G04CA01

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 parameters by reducing urethral tone and bladder outlet resistance, and facilitates bladder emptying.

In placebo controlled studies in BPH patients, alfuzosin:

significantly increases peak flow rate (Q_max) in patients with Q_max <15 ml/s by a mean of 30%. This improvement is observed from the first dose.
significantly reduces the detrusor pressure and increases the volume producing a strong desire to void.
significantly reduces 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 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

Alfuzosin Orion 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 interindividual 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 people have higher bioavailability, which leads to higher maximum plasma concentrations but unchanged half-life.

.5.3Preclinical safety data

Non-clinical data reveal no special hazard for humans.

6Pharmaceutical Particulars

.6.1List of excipients

Tablet core:

Sodium starch glycolate (Type A)

Cellulose, microcrystalline

Lactose monohydrate

Povidone

Magnesium stearate

Film-coating:

Hypromellose

Macrogols

Titanium dioxide (E 171)

.6.2Incompatibilities

Not applicable.

.6.3Shelf life

2years.

.6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

.6.5Nature and contents of container

PVC / PVdC- Aluminium foil blister: 30 and 90 tablets.

HDPE container with polypropylene screw cap: 100 tablets.

Not all pack sizes may be marketed.

.6.6Special precautions for disposal

No special requirements.

7Marketing Authorisation Holder

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

8MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9Date of First Authorisation/Renewal of the Authorisation

Date of first authorisation: -

Date of latest renewal: -

10Date of Revision of the Text

20 May 2016