FARAMSIL 400 MICROGRAMSPROLONGED-RELEASE TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Faramsil 400 microgram Prolonged-release Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 0.4 mg of tamsulosin hydrochloride.

Excipients with known effect

Each prolonged-release tablet contains 17.8 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

Brown, round, biconvex tablet with debossing “0.4” on one side and “SZ” on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

4.2 Posology and method of administration

Posology

One tablet daily can be taken independently of food.

Method of administration

For oral use.

The tablet should be swallowed whole and should not be crushed or chewed as this will interfere with the prolonged release of the active ingredient.

Special populations

Renal impairment: no dose adjustment is required in patients with renal impairment

Hepatic impairment: no dose adjustment is required in patients with mild to moderate hepatic impairment (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

4.3 Contraindications

Hypersensitivity to tamsulosin, 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 alpha1-blockers, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, leading in rare cases to syncope. At the first signs of orthostatic hypotension (dizziness, weakness), the patient should sit or lie down until the symptoms have disappeared.

Prior to commencement of therapy with tamsulosin, the patient should be examined in order to exclude the presence of other conditions which may produce similar symptoms to those of benign prostatic hyperplasia. Digital rectal examination and, when necessary, determination of prostate specific antigen (PSA) should be performed prior to commencement of treatment and at regular intervals afterwards.

The treatment of patients with severe renal impairment (creatinine clearance 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. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with tamsulosin in patients scheduled for cataract or glaucoma surgery is not recommended.

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

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

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

Faramsil contains lactose and sodium

Tamsulosin prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) sodium per prolonged-release tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

No interactions have been seen when tamsulosin was given concomitantly with atenolol, enalapril or theophylline. Concomitant cimetidine increases and concomitant furosemide lowers plasma levels of tamsulosin, however, 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 with strong inhibitors of CYP3A4 may lead to increased exposure to tamsulosin. Concomitant administration with ketoconazole (a known strong CYP3A4 inhibitor) resulted in an increase in AUC and Cmax of tamsulosin by a factor of 2.8 and 2.2, respectively.

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

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

Concomitant administration of tamsulosin 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 concomitantly with drugs which may reduce blood pressure, including anaesthetic agents and other alpha1– adrenoreceptors antagonists.

4.6 Fertility, pregnancy and lactation

Tamsulosin 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 authorization pha­se.

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 drowsiness, blurred vision, dizziness and syncope can occur.

4.8 Undesirable effects

Tamsulosin prolonged-release tablets were evaluated in two double-blind placebo controlled trials. Adverse events were mostly mild and their incidence was generally low. The most commonly reported ADR was abnormal ejaculation occurring in approximately 2% of patients.

Suspected adverse reactions reported with Tamsulosin prolonged release tablets or an alternative formulation of tamsulosin, were:

Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100) Rare (>1/10,000 to <1/1,000) and Very rare (<1/10,000), including isolated reports , not known (frequency cannot be estimated from the available data).

Nervous systems disorders

Common: dizziness (1.3%)

Uncommon: headache

Rare: syncope

Eye disorders

Not known: vision blurred*, visual impairment*

Cardiac disorders

Uncommon: palpitations

Vascular disorders

Uncommon: orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon: rhinitis

Not known: epistaxis*

Gastrointestinal disorders

Uncommon: nausea, vomiting, constipation, diarrhoea

Not known: dry mouth*

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, urticaria

Rare: angioedema

Very rare: Stevens-Johnson syndrome

Not known: erythema multiforme*, dermatitis exfoliative*

Reproductive system and breast disorders

Common: ejaculation disorders including retrograde ejaculation and ejaculation failure

Very rare: priapism

General disorders and administration site conditions

Uncommon: asthenia

*observed post-marketing

As with other alpha-blockers, drowsiness, blurred vision, dry mouth 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 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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

Symptoms

Overdosage with tamsulosin 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 overdose, cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this is insufficient 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

Alpha adrenoceptor antagonists.

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 alpha1A, resulting in relaxation of the smooth muscle of the prostate, whereby tension is reduced.

Pharmacodynamic effects

Tamsulosin increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, 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.

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 a prolonged-release tablet is absorbed from the intestine and its bioavailability is approximately 55–59% A consistent slow release of tamsulosin is maintained over the whole pH range encountered in the gastro-intestinal tract with little fluctuation over 24 hours. The rate and extent of absorption of tamsulosin administered as a prolonged release-tablet is not affected by food intake.

Tamsulosin shows linear kinetics.

Following administration of a single dose of tamsulosin in fasting state, plasma levels of tamsulosin peak at a median time of 6 hours. At steady state, which is reached by day 4 of multiple dosing, plasma levels of tamsulosin peak at 4 to 6 hours in fasting and fed state. Peak plasma levels increase from approximately 6 ng/ml after the first dose to 11 ng/ml at steady state.

As a result of the prolonged release characteristics of the tablet the trough concentration of tamsulosin in plasma amounts to 40% of the peak plasma concentration under fasting and fed conditions.

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

Distribution

In male patients, tamsulosin is about 99% bound to plasma proteins and the volume of distribution is small (about 0.2l/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.

Elimination

Tamsulosin and its metabolites are mainly excreted in the urine. The urinary recovery of unchanged drug is estimated to be about 4–6% of the dose, administered as a prolonged release tablet

After a single dose of tamsulosin, and at steady state, elimination half-life of about 19 and 15 hours, respectively, has 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 clinically irrelevant. Tamsulosin showed no relevant genotoxic properties.

Increased incidences of proliferative changes of mammary glands of female rats and mice have been reported. These findings appeared to be related to hyperprolactinaemia and only occurred at high dose levels, are regarded as irrelevant.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Cellulose, microcrystalline

Hydroxypropyl­cellulose

Lactose monohydrate

Polyethylene oxide

Butylhydroxytoluene

Magnesium stearate

Silica, colloidal anhydrous

Tablet film-coating

Hypromellose

Hydroxypropyl­cellulose

Macrogol 400

Titanium dioxide (E 171)

Talc

Quinoline yellow (contains sodium) (E 104)

Carmine (E 120)

Iron oxide, black (E 172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

Aluminium//Alu­minium blisters.

Pack sizes: 10, 14, 20, 28, 30, 50, 56, 60, 80, 90, 100 and 200 prolonged-release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Sandoz Limited

Park View, Riverside Way Watchmoor Park

Camberley, Surrey

GU15 3YL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04416/0987

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 14 July 2011

Date of latest renewal: 08 June 2016