SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Sulatamin 0.4 mg prolonged-release capsules, hard

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 0.4 mg tamsulosin hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release capsule, hard.

White or off-white pellets are filled in the capsules with size No. 2 (about 18 mm lengthwise and 6.3 mm in external diameter), which upper part is brown opaque, lower part is buff opaque.

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

Posology

One capsule daily.

Use in renal impairment

No dose adjustment is warranted in renal impairment (see section 4.4).

Use in hepatic impairment

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

Paediatric population

There is no relevant use of Sulatamin in the paediatric population.

Method of administration

For oral use. One capsule daily, to be taken after breakfast or the first meal of the day. The capsule must be swallowed whole and must not be crunched or chewed as this interferes with the prolonged release of the active substance.

Contraindications

-    Hypersensitivity to the active substance (including tamsulosin-induced angio-edema) or to any of the excipients listed in section 6.1.

-    Orthostatic hypotension observed earlier (history of orthostatic hypotension).

-    Severe hepatic insufficiency.

4.4 Special warnings and precautions for use

As with other ai-adrenoceptor 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 severe renal impairment (creatinine clearance of < 10 ml/min) should be approached with caution, as these patients have not been studied.

Angio-oedema has been rarely reported after the use of tamsulosin. Treatment should be discontinued immediately, 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. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with tamsulosin in patients for whom cataract surgery is scheduled is not recommended.

Discontinuing tamsulosin 1-2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping of therapy prior to cataract surgery has not yet been established.

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.

4.5 Interaction with other medicinal products and other forms of interaction

No interactions have been seen when tamsulosin was given concomitantly with either atenolol, enalapril, or theophylline.

Concomitant use of cimetidine brings about a rise in plasma levels of tamsulosin, but as level remains within the normal range posology need not be adjusted.

Whereas concomitant use of furosemide brings a fall in plasma levels of tamsulosin, but as level remains 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.

No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions (representative of the cytochrome P₄₅₀-linked drug metabolising enzyme system), involving amitriptyline, salbutamol, glibenclamide and finasteride.

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 ai-adrenoceptor antagonists could lead to hypotensive effects.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, Pregnancy and lactation

Pregnancy and lactation

Not applicable as tamsulosin is intended for male patients only. For more information see section 5.3.

Fertility

Ejaculation disorder may occur following treatment with tamsulosin (see section 4.8) and may consequently have an effect on fertility (see section 5.3).

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.

4.8 Undesirable effects

The adverse reactions are described according to the MedDRA system organ class in the table below.

Frequencies in the list are defined using the following convention:

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)

MedDRA System Organ Class	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 )
Nervous system disorders	Dizziness (1.3%)	Headache	Syncope
Cardiac disorders		Palpitations
Vascular disorders		Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders		Rhinitis
Gastrointesti nal disorders		Constipation, Diarrhoea, Nausea, Vomiting
Skin and subcutaneou s tissue disorders		Rash, Pruritus, Urticaria	Angioedema	Stevens- Johnson syndrome
Reproductiv e system and breast disorders	Ejaculation disorder			Priapism
General disorders and administrati on 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 section 4.4).

Post-marketing experience

In addition to the adverse events listed above, atrial fibrillation, arrhythmia, tachycardia and dyspnoea have been reported in association with tamsulosin use. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of tamsulosin in their causation cannot be reliably determined.

4.9 Overdose

Acute overdose with 5 mg of tamsulosin has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed, which were treated with fluid replacement and the patient could be discharged the same day.

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. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals, Alpha-adrenoreceptor antagonists (preparations for the exclusive treatment of prostatic disease), ATC code: G04CA02

Mechanism of action

Tamsulosin binds selectively and competitively to the postsynaptic a₁-adrenoceptors, in particular to subtypes a_1A and a_1D. It brings about relaxation of prostatic and urethral smooth muscle.

Pharmacodynamic effects

Tamsulosin increases the maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in prostate and urethra thereby improving voiding symptoms.

It also improves the storage symptoms in which bladder instability plays an important role.

These effects on storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterisation is significantly delayed.

a₁-adrenoceptor antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.

5.2 Pharmacokinetic properties

Absorption

Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Absorption of tamsulosin is reduced by a recent meal. Uniformity of absorption can be promoted by the patient always taking tamsulosin after breakfast or the first meal of the day. Tamsulosin shows linear kinetics.

After a single dose of tamsulosin in the fed state, plasma levels of tamsulosin peak at around 6 hours and, in the steady state, which is reached by day 5 of multiple dosing, C_max in patients is about two thirds higher than that reached after a single dose. Although this was seen in elderly patients, the same finding would also be expected in young ones.

There is a considerable inter-patient variation in plasma levels both after single and multiple dosing.

Distribution

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

Biotransformation

Tamsulosin has a low first pass effect, being metabolised slowly. Most tamsulosin is present in plasma in the form of unchanged drug. It is metabolised in the liver. In rats, hardly any induction of microsomal liver enzymes was seen to be caused by tamsulosin. None of the metabolites are more active than the original compound.

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

Elimination

Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of a dose being present in the form of unchanged drug. After a single dose of tamsulosin in the fed state, and in the steady state in patients, elimination half-lives of about 10 and 13 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 known pharmacological actions of the alpha-adrenergic blocking agents. At very high dose levels the ECG was altered in dogs. This response is considered to be not clinically relevant. Tamsulosin showed no relevant genotoxic properties.

During carcinogenicity studies, increased incidences of proliferative changes of 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.

An increased incidence of thrombus formation in the left atrium was also noted in the rat, at exposures that were similar to those observed clinically; however, the clinical relevance of this finding is unknown.

Studies in rats revealed significantly reduced fertility in males dosed with single or repeated doses of tamsulosin hydrochloride at 300 mg/kg/day. No significant effect on male fertility was observed following repeated doses of 10 and 100 mg/kg/day.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule content:

Microcrystalline cellulose,

Methacrylic acid - ethyl acrylate copolymer (1:1) dispersion 30 per cent (including: polysorbate 80, sodium laurilsulfate),

Talc,

Triethyl citrate,

Calcium stearate.

Capsule shell:

Yellow iron oxide (E172), Black iron oxide (E172), Red iron oxide (E172), Titanium dioxide (E171), Gelatin.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

30, 90 or 100 capsules are packed into clear or white opaque PVC/PVDC//Aluminium blisters.

The blisters are packed into folding box with a package leaflet. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Gedeon Richter Plc.

Gyomroi ut 19-21.

1103 Budapest, Hungary

8    MARKETING AUTHORISATION NUMBER(S)

PL 04854/0135

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/10/2012

10 DATE OF REVISION OF THE TEXT

15/01/2014