SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Brundeel XL 400 microgram Prolonged-Release Hard Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release capsule contains 0.4 mg of tamsulosin hydrochloride. For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release capsule, hard

Olive green opaque/ Orange opaque size ‘0’ hard gelatin capsules imprinted with ‘D’ on cap and ‘53’ on body with black edible ink filled with white to off-white beadlets.

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

For oral use.

Adults:

One capsule a day after breakfast or the first meal of the day. The capsule is swallowed whole with a glass of water while standing or sitting (not lying down). The capsule should not be broken or pulled apart as this may have an effect on the release of the long-acting active ingredient.

Elderly patients:

Dose reduction is not necessary.

Patients with renal impairment:

In patients with creatinine clearance over 0.17 ml/sec. (10 ml/min) there is no need of dosage modification.

Patients with hepatic impairment:

In patients with mild to moderate liver dysfunction there is no need of dosage modification (see also 4.3, contraindications).

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 hydrochloride, 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 i-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.

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. 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 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 schedules 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 (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 seen when tamsulosin hydrochloride was 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, chlormadinon, 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 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 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 Fertility, pregnancy and lactation

Not applicable as tamsulosin is intended for male patients only.

4.8 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)
Nervous system disorders	Dizziness (1.3%)	Headache	Syncope
Cardiac disorders		Palpitations
Vascular disorders		Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders		Rhinitis
Gastrointestinal disorders		Constipation, diarrhoea, nausea, vomiting
Skin and subcutaneous tissue disorders		Rash, pruritus, urticaria	Angio-oedema	Stevens- Johnson syndrome
Reproductive systems and breast disorders	Ejaculation disorders			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, 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 tamsulosin hydrochloride 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.

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.

4.10 Overdose

Acute overdose with 5 mg tamsulosin hydrochloride 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: Drugs used in benign prostatic hypertrophy, Alpha-adrenoreceptor antagonists, ATC code: G04CA02

Mechanism of action

Tamsulosin binds selectively and competitively to postsynaptic a1A adrenoreceptors, which convey smooth muscle contraction, thereby relaxing prostatic and urethral smooth muscle.

Pharmacodynamic effects

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 tamsulosine 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 is rapidly 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 always taking tamsulosin after breakfast.

Tamsulosin shows linear kinetics.

Peak plasma levels are achieved at approximately six hours after a single dose of tamsulosin taken after a full meal. The steady state is reached by day five of multiple dosing, when Cmax in patients is about two-thirds higher than that reached after a single dose. Although this has been demonstrated only in the elderly, the same result would also be expected in younger patients.

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 urine with about 9% of the dose being present in unchanged form.

The elimination half-life of tamsulosin in patients is approximately 10 hours (when taken after a meal) and 13 hours in the steady state.

5.3 Preclinical safety data

Toxicity after a single dose and multiple dosing has been investigated in mice, rats and dogs. Reproductive toxicity has also been investigated in rats, carcinogenicity in mice and rats, and genotoxicity in vivo and in vitro.

The common toxicity profile found with large doses of tamsulosin is equivalent to the pharmacological effect associated with alpha adrenergic antagonists. Changes in ECG readings were found with very large doses in dogs. This is not, however, assumed to be of any clinical significance. Tamsulosin has not been found to have any significant genotoxic properties.

Greater proliferative changes in the mammary glands of female rats and mice have been discovered on exposure to tamsulosin. These findings, which are probably indirectly linked to hyperprolactinaemia and only occur as a result of large doses having been taken, are considered clinically insignificant.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule Contents

Cellulose, microcrystalline Talc

Methacrylic acid-ethyl acrylate copolymer

Sodium lauryl sulfate

Polysorbate 80

Triacetin

Calcium stearate

Capsule shell

Indigo carmine (E132)

Iron oxide red (E172) Iron oxide yellow (E172) Titanium dioxide (E171) Gelatin

Sodium lauryl sulfate Printing Ink

Shellac

Propylene glycol Black iron oxide (E172) Potassium hydroxide

6.2    Incompatibilities

Not applicable

6.3    Shelf life

2 years

6.4    Special precautions    for storage

This medicinal product does not require any special temperature storage conditions

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

6.5    Nature and contents of container

PVC/PE/PVDC/Aluminium blister packs

Blister: 10, 20, 30, 50, 60, 90, 100 or 200 capsules

White opaque round HDPE bottle with white opaque polypropylene closure:

250 capsules.

Not all pack sizes may be marketed

6.6    Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Amneal Pharma Europe Limited 70 Sir John Rogerson’s Quay,

Dublin 2,

Ireland.

8    MARKETING AUTHORISATION NUMBER(S)

PL 42357/0126

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/05/2012

10    DATE OF REVISION OF THE TEXT

19/06/2014