SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Flectone XL 400 microgram prolonged-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One prolonged-release tablet contains 0.40 mg tamsulosin hydrochloride equivalent to 0.367 mg tamsulosin.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet

Yellow, biconvex, oval, film-coated tablet, debossed 'T04' on one side and plain on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

4.2 Posology and method of administration

One prolonged-release (PR) tablet daily.

No dose adjustment is warranted in renal impairment.

No dose adjustment is warranted in patients with mild to moderate hepatic insufficiency (see also section 4.3).

Paediatric population

The safety and efficacy of tamsulosine in children <18 years have not been established. Currently available data are described in section 5.1.

Method of administration

The tablet can be taken independently of food and must be swallowed whole and not crunched or chewed as this interferes with the prolonged release of the active substance

4.3 Contraindications

Hypersensitivity to tamsulosin, including drug-induced angioedema, or to any of the excipients listed in section 6.1.

History of orthostatic hypotension.

Severe hepatic insufficiency.

4.4 Special warnings and precautions for use

As with other a 1-adrenoceptors antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, as a result of which, rarely, syncope can occur. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared.

Before therapy with tamsulosin is initiated, the patient should be examined in order to exclude the presence of other conditions, which can cause the same symptoms as benign prostatic hyperplasia. Digital rectal examination and, when necessary, determination of prostate specific antigen (PSA) should be performed before treatment and at regular intervals afterwards.

The treatment of patients with severely impaired renal function (creatinine clearance of < 10 ml/min) should be approached with caution as these patients have not been studied.

Angioedema has been rarely reported after the use of tamsulosin. Treatment should be discontinued immediately, the patient should be monitored until disappearance of the oedema, and tamsulosin should not be re-administered.

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 hydrochloride. IFIS may increase the risk of eye complications during and after the operation.

Discontinuing Flectone XL 1-2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not yet been established. IFIS has also been reported in patients who had discontinued tamsulosin for a longer period prior to cataract surgery.

The initiation of therapy with tamsulosin hydrochloride in patients for whom cataract surgery is scheduled is not recommended. During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with tamsulosin in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Tamsulosin hydrochloride should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype.

Tamsulosin hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4 (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Interactions studies have only been performed in adults.

No interactions have been seen when tamsulosin hydrochloride has been given concomitantly with either atenolol, enalapril, or theophylline. Concomitant cimetidine brings about a rise in plasma levels of tamsulosin, whereas furosemide a fall, but as levels remain within the normal range posology need not be adjusted.

In vitro, neither diazepam nor propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin and warfarin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide and chlormadinone.

Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin.

Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 may lead to increased exposure to tamsulosin hydrochloride. Concomitant administration with ketoconazole (a known strong CYP3A4 inhibitor) resulted in an increase in AUC and Cmax of tamsulosin hydrochloride by a factor of 2.8 and 2.2, respectively.

Tamsulosin hydrochloride should not be given in combination with strong inhibitors of CYP3A4 in patients with poor metaboliser CYP2D6 phenotype.

Tamsulosin hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4.

Concomitant administration of tamsulosin hydrochloride with paroxetine, a strong inhibitor of CYP2D6, resulted in a Cmax and AUC of tamsulosin that had increased by a factor of 1.3 and 1.6, respectively, but these increases are not considered clinically relevant.

Concurrent administration of other a 1-adrenoceptor antagonists could lead to hypotensive effects.

4.6    Pregnancy and lactation

Flectone XL is is not indicated for use in women.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be aware of the fact that dizziness can occur.

Undesirable effects

	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
Nervous system disorders	Dizziness (1.3%)	Headache	Syncope
Eye disorders					Vision blurred, visual impairment
Cardiac disorders		Palpitations
Vascular disorders		Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders		Rhinitis			Epistaxis
Gastrointestina l disorders		Constipation, diarrhoea, nausea, vomiting			Dry mouth
Skin and subcutaneous tissue disorders		Rash, itching, urticaria	Angioedema	Stevens- Johnson syndrome	Erythema multiforme, dermatitis exfoliative
Reproductive and breast disorders	Ejaculation disorders, Retrograde ejaculation, Ejaculation failure			Priapism
General disorders and administration site conditions		Asthenia

During cataract surgery a small pupil situation, known as Intraoperative Floppy Iris Syndrome (IFIS), has been associated with therapy of tamsulosin during postmarketing surveillance (see also section 4.4).

Post-marketing experience: In addition to the adverse events listed above, the following have been reported in associateion with tamsulosin use:

Cardiac disorders

Not known: Atrial fibrillation, arrhythmia, tachycardia

Respiratory, thoracic and mediastinal disorders:

Not known: Dyspnoea

Since these spontaneously reported events are from worldwide post marketing experience, their frequency and the role of tamsulosin in their causation cannot be reliably determined.

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 Symptoms

Overdosage with tamsulosin hydrochloride can potentially result in severe hypotensive effects. Severe hypotensive effects have been observed at different levels of overdosing.

Treatment

In case of acute hypotension occurring after overdosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders and, when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied.

Dialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins.

Measures such as emesis can be taken to impede absorption. If large quantities of the medicinal product are involved, gastric lavage may be performed and activated charcoal and an osmotic laxative, such as sodium sulphate, may be given.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists ATC code: G04CA02

The medicinal product is only used for the treatment of prostatic conditions.

Mechanism of action

Tamsulosin binds selectively and competitively to post-synaptic oq-adrenoreceptors, in particular to the subtypes a_1A and a_1D, which brings about relaxation of prostatic and urethral smooth muscle.

Tamsulosin increases the maximum urinary flow rate by relaxing prostatic and urethral smooth muscle, thus relieving obstruction.

The medicinal product also improves the irritative and obstructive symptoms in which the contraction of smooth muscle in the lower urinary tract plays an important role.

Alpha-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin in normotensive patients.

The medicinal product’s effect on storage and voiding symptoms are also maintained during long-term therapy. Observational data indicate that use of tamsulosin may lead to a delay in the need for surgery or catheterization.

Paediatric population

A double-blind, randomized, placebo-controlled, dose ranging study was performed in children with neuropathic bladder. A total of 161 children (with an age of 2 to 16 years) were randomized and treated at 1 of 3 dose levels of tamsulosin (low [0.001 to 0.002 mg/kg], medium [0.002 to 0.004 mg/kg], and high [0.004 to 0.008 mg/kg]), or placebo. The primary endpoint was number of patients who decreased their detrusor leak point pressure (LPP) to <40 cm H2O based upon two evaluations on the same day. Secondary endpoints were: Actual and percent change from baseline in detrusor leak point pressure, improvement or stabilization of hydronephrosis and hydroureter and change in urine volumes obtained by catheterisation and number of times wet at time of catheterisation as recorded in catheterisation diaries. No statistically significant difference was found between the placebo group and any of the 3 tamsulosin dose groups for either the primary or any secondary endpoints. No dose response was observed for any dose level.

5.2 Pharmacokinetic properties

Absorption

Tamsulosin administered as prolonged-release tablets is absorbed from the intestine. Of the administered dose, approximately 57% is estimated to be absorbed. The rate and extent of absorption of tamsulosin administered as prolonged-release tablets are not affected by food.

Tamsulosin shows linear kinetics.

After a single dose of tamsulosin prolonged-release tablets in the fasted state, plasma concentrations of tamsulosin peak at a median time of 6 hours. In steady-state, which is reached by day 4 of multiple dosing, plasma concentrations of tamsulosin peak at 4 to 6 hours, in the fasted and fed state. Peak plasma concentrations increase from approximately 6 ng/ml after the first dose to 11 ng/ml in steady-state. As a result of the prolonged-release characteristics of these tablets the trough concentration of tamsulosin in plasma amounts to 40% of the peak plasma concentration under fasted and fed conditions.

There are huge inter-patient variations in plasma levels of tamsulosin, both after single as well as multiple dosing.

Distribution

In humans, tamsulosin is more than 99% bound to plasma proteins and the volume of distribution is small (about 0.2 l/kg).

Biotransformation

Tamsulosin has a low first-pass metabolic effect. Most tamsulosin is found unaltered in plasma. The substance is metabolised in the liver.

In studies on rats, tamsulosin was found to cause only a slight induction of microsomal liver enzymes.

The metabolites are not as effective and toxic as the active medicinal product itself. Elimination

Tamsulosin and its metabolites are mainly excreted in the. The amount excreted as unchanged active substance is estimated to be about 4-6% of the dose, administered as prolonged-release tablets.

After a single dose of tamsulosin as prolonged-release tablets and in steady-state, elimination half-lives of about 19 and 15 hours, respectively, have been measured.

5.3 Preclinical safety data

Single- and repeat dose toxicity studies were performed in mice, rats and dogs. In addition reproduction toxicity studies were performed in rats, carcinogenicity in mice and rats and in vivo and in vitro genotoxicity were examined.

The general toxicity profile as seen with high doses of tamsulosin is consistent with the pharmacological actions of alpha-adrenergic blocking agents.

At very high dose levels, the ECG was altered in dogs. This response is not considered to be clinically relevant. Tamsulosin showed no relevant genotoxic properties.

Increased incidences of proliferative changes in the mammary glands of female rats and mice have been reported. These findings, which are probably mediated by hyperprolactinaemia and only occurred at high dose levels are regarded as irrelevant.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:    Cellulose microcrystalline

Film-coating:

Polyethylene oxide Silica, colloidal anhydrous Magnesium stearate Hypromellose 6cP Titanium dioxide (E171) Macrogol 8000 Iron oxide, yellow (E172) Iron oxide, red (E172)

6.2    Incompatibilities

Not applicable

6.3    Shelf life

36 months

6.4    Special precautions for    storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

OPA/Alu/PVC-aluminium blister

Pack sizes:    10, 14, 20, 28, 30, 50, 56, 60, 90, 100, 200 Tablets and 50x1 (hospital

pack) prolonged-release tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne BN22 9AG United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1142

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 23/05/2011

10 DATE OF REVISION OF THE TEXT

14/03/2014