SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tamsulosin Hydrochloride 400 micrograms MR Capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One capsule contains 400 micrograms of tamsulosin hydrochloride.

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Modified-release capsule, hard

Hard gelatin capsules with orange coloured body and olive coloured cap.. The capsules are filled with white to off-white pellets.

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, to be taken after breakfast or the first meal of the day.

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

Paediatric population

There is no relevant indication for use of tamsulosin in children. 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 capsule must be swallowed whole and must not be crushed or chewed as this interferes with the modified release of the active ingredient.

4.3 Contraindications

Hypersensitivity to the active substance, including drug-induced angio-oedema, or to any of the excipients listed in section 6.1.

A 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 severe renal impairment (creatinine clearance of < 10 ml/min) should be approached with caution as these patients have not been studied.

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 tamsulosin hydrochloride 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

Interaction studies have only been performed in adults.

No interactions have been observed when tamsulosin has been given concomitantly with atenolol, enalapril, or theophylline. Concomitant cimetidine raises, and concomitant furosemide lowers, plasma concentrations of tamsulosin but, as the concentration of tamsulosin remains within the normal range, posology need not be altered.

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.

Tamsulosin has not been found to interact with amitriptyline, salbutamol, glibenclamide or finasteride during in vitro studies with liver microsomal fractions (representing the cytochrome P450-linked metabolising enzyme system). Diclofenac and Warfarin may increase the elimination rate of tamsulosin.

Concurrent administration with another a₁-adrenoreceptor antagonist may lower blood pressure.

4.6 Fertility, pregnancy and lactation

Tamsulosin is intended for males only.

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

The frequencies of adverse reactions are ranked according to the following: 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).

	Common	Uncommon	Rare	Very rare	Not known
Nervous system disorders	Dizziness	Headache	Syncope
Eye disorder					vision blurred, visual impairment
Cardiac disorders		Palpitations
Vascular disorders		Orthostatic hypotension
Respiratory, thoracic and mediastinum-related disorders		Rhinitis			epistaxis
Gastrointestinal disorders		Constipation , diarrhoea, nausea, vomiting			Dry mouth
Skin and subcutaneous tissue disorders		Rash, itching, urticaria	Angio- oedema	Stevens- Johnson syndrome	erythema multiforme, dermatitis exfoliative
Reproductive systems and breast disorders	Ejaculation disorder, 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 post-marketing surveillance (see section 4.4).

Post-marketing experience

In addition to the adverse events listed above, the following adverse reactions have been reported in association with tamsulosin use:

Cardiac disorders

Not Known: Atrial fibrillation, arrhythmia, tachycardia

Respiratory, thoracic and mediastinal disorders Not known: Dyspnoea

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.

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.

Management

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: a_{1 -} adrenoreceptor antagonist. ATC code: G04CA02

Preparations for the exclusive treatment of prostatic disease.

Mechanism of action

Tamsulosin binds selectively and competitively to postsynaptic ai . adrenoreceptors, 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 relives 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 catheterization is significantly delayed.

a ^adrenoceptors antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.

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 is absorbed from the intestines and its bioavailability is almost complete. Absorption is slowed down if a meal has been eaten before taking the medicinal product. Uniformity of absorption can be assured by the patient always taking tamsulosin after the same meal.

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. The volume of distribution is small (about 0.2 l/kg).

Biotransformation

Tamsulosin has a low first pass effect, being metabolized slowly. Most tamsulosin is present in plasma in the form of unchanged active substance. It is metabolised in the liver.

In rats, hardly any induction of microsomal liver enzymes was seen to be caused by tamsulosin.

In vitro results suggest that CYP3A4 and also CYP2D6 are involved in metabolism, with possible minor contributions to tamsulosin hydrochloride metabolism by other CYP isozymes. Inhibition of CYP3A4 and CYP2D6 drug metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride (see section 4.4 and 4.5).

None of the metabolites are more active than the original compound. Elimination

Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of the dose being present in the form of unchanged active substance.

After a single dose of tamsulosin 0.4 mg in the fed state, and in the steady state in patients, elimination half-lifes 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 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 a i-adrenoceptors antagonists.

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.

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

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Content of capsule

Microcrystalline cellulose

Methacrylic acid-ethyl acrylate copolymer

Polysorbate 80

Sodium laurilsulfate

Triethyl citrate

Talc

Capsule body

Gelatine

Indigotine (E 132)

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

6.2    Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

6.4 Special precautions for storage

Blister packs: Store in the original package.

Tablet containers: Keep the container tightly closed.

6.5    Nature and contents of container

PVC/PE/PVDC/Aluminium blister packs in cardboard boxes and HDPE tablet containers with PP child-resistant closures containing 10, 14, 20, 28, 30, 50, 56, 60, 90, 100, 180 or 200 modified-release capsules.

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 East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0860

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

02/02/2006

10 DATE OF REVISION OF THE TEXT

02/11/2016