SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tamsumac 0.4 mg prolonged release capsules, hard

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each capsule contains as active ingredient tamsulosin hydrochloride 0.4 mg, equivalent to 367 microgram tamsulosin.

Excipient(s)

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Prolonged release capsules, hard

Olive green opaque / Orange opaque, Size "2", hard gelatin capsules, containing free flowing white to off white spheroids with "CL 23" on cap and "0.4" on the body imprinted with black ink.

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

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 ingredient.

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

Paediatric population

There is no relevant indication for use of Tamsumac 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

4.3 Contraindications

Hypersensitivity to tamsulosin hydrochloride, including drug-induced angioedema or to any of the excipients.

A history of orthostatic hypotension.

Severe hepatic insufficiency.

4.4 Special warnings and precautions for use

As with other alpha1-blockers, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin hydrochloride, 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 hydrochloride 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 severely renally impaired patients (creatinine clearance of less than 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 and glaucoma 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 or glaucoma 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 the surgery.

The initiation of therapy with tamsulosin hydrochloride in patients for whom cataract or glaucoma surgery is scheduled is not recommended. During pre-operative assessment, surgeons and ophthalmic teams should consider whether patients scheduled for cataract or glaucoma 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 (e.g. ketoconazole) in patients with poor metaboliser CYP2D6 phenotype.

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

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 cimetidine brings about a rise in plasma levels of tamsulosin and furosemide a fall, but as levels remain within the normal range posology need not be changed.

In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, 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 chlormadinon.

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 (e.g. ketoconazole) in patients with poor metaboliser CYP2D6 phenotype.

Tamsulosin hydrochloride should be used with caution in combination with strong (e.g. ketoconazole) and moderate inhibitors (e.g. erythromycin) 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.

There is a theoretical risk of enhanced hypotensive effect when given concurrently with drugs which may reduce blood pressure, including anaesthetic agents and other a₁-adrenoceptor antagonists.

4.6 Fertility, pregnancy and lactation

Tamsumac is not indicated for use in women.

Ejaculation disorders have been observed in short and long term clinical studies with tamsulosin. Events of ejaculation disorder, retrograde ejaculation and ejaculation failure have been reported in the post authorisation phase.

4.7 Effects on ability to drive and use machines

No data is available on whether Tamsumac adversely affects the ability to drive or operate machines. However, in this respect patients should be aware of the fact that drowsiness, blurred vision, dizziness and syncope can occur.

4.8 Undesirable effects

System Organ Class	Common >1/100, <1/10	Uncommon >1/1000, <1/100	Rare >1/10,000, <1/1000	Very rare <1/10,000	Not known (cannot be estimated from the available data)
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*
Gastro intestinal disorders		constipation, diarrhoea, nausea, vomiting			Dry mouth*
Skin and subcutaneous tissue		rash, pruritus,	angioedema	Stevens- Johnson	Erythema multiforme*

disorders		urticaria		syndrome	Dermatitis exfoliative*
Reproductive systems and breast disorders	ejaculation disorders, including retrograde ejaculation and ejaculation failure			priapism
General disorders and administration site conditions		asthenia

*observed post-marketing

As with other alpha-blockers, drowsiness, blurred vision or oedema can occur.

During cataract and glaucoma surgery a small pupil situation, known as Intraoperative Floppy Iris Syndrome (IFIS), has been associated with therapy of tamsulosin during post-marketing surveillance (see also 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.

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 www.mhra.gov .uk/yellowcard.

4.9 Overdose

Symptoms

Overdosage with tamsulosin hydrochloride can potentially result in severe hypotensive effects, dizziness and malaise. 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. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulfate, can be administered.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group:

Alpha₁-adrenoceptor antagonist, ATC code: G04C A02. Preparations for the exclusive treatment of prostatic disease.

Mechanism of action:

Tamsulosin binds selectively and competitively to postsynaptic alpha₁-receptors, in particular to the subtype alpha_1A, which bring about relaxation of the smooth muscle of the prostate, whereby tension is reduced.,

Pharmacodynamic effects:

Tamsulosin hydrochloride increases maximum urinary flow rate by reducing smooth muscle

tension in prostate and urethra and thereby relieving obstruction.

It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role.

Alpha₁-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin hydrochloride.

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 catheterization 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 hydrochloride is absorbed from the intestine and is almost completely bioavailable.

Absorption of tamsulosin hydrochloride is reduced by a recent meal.

Uniformity of absorption can be promoted by the patient always taking Tamsumac after the same meal each day.

Tamsulosin shows linear kinetics.

After a single dose of Tamsumac 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, Cmax 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.

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 metabolising enzymes may lead to increased exposure to tamsulosin hydrochloride (see sections 4.4 and 4.5).

No dose adjustment is warranted in hepatic insufficiency.

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 a dose being present in the form of unchanged drug.

After a single dose of Tamsumac in the fed state, and in the steady state in patients, elimination half-lives of about 10 and 13 hours respectively have been measured.

The presence of renal impairment does not warrant lowering the dose.

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.

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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Content of capsule:    Polysorbate 80

Methacrylic Acid Copolymer Dispersion Triacetin

Sodium Lauryl Sulfate Purified water Microcrystalline Cellulose Calcium stearate

Capsule shell:    FD & C Blue 2 (E 132)

Iron oxide black (E 172)

Iron oxide red (E 172)

Iron oxide yellow (E 172)

Titanium dioxide (E 171)

Gelatin

Purified Water Sodium lauryl sulfate

Printing ink:    Shellac (E904)

Dehydrated alcohol Isopropyl alcohol Butyl alcohol Propylene glycol Strong Ammonia solution Black Iron Oxide (E172)

Potassium Hydroxide

Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister pack: Clear Film PVC/PE/PVdC film / Aluminium foil in a carton box. Pack size: 14, 20, 28, 30, 50, 56, 90, 98 and 100 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Macleods Pharma UK Limited,

Wynyard Park House,

Wynyard Avenue,

Wynyard, Billingham,

TS22 5TB, United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 34771/0170

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 23/06/2016

DATE OF REVISION OF THE TEXT

23/06/2016