Tamsulosin 400 micrograms modified-release capsules, hard

1.  NAME OF THE MEDICINAL PRODUCT

Tamsulosin 400 micrograms modified Modified-release capsules Capsules, hard Hard

3. PHARMACEUTICAL FORM

Modified-release capsule, hard

Orange body/olive-green capsule cap. The capsules contain white to off-white pellets spheres.

4.2 Posology and method of administration

Posology

One capsule a day to be taken after breakfast or the first meal of the day.

Patients with renal impairment
No dose adjustment is warranted in renal impairment.

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

Paediatric population

The safety and efficacy of tamsulosin in children < 18 years have not been established. Currently available data are described in section 5.1.

Method of administration

For oral use.

The capsule is must be swallowed whole and must not be crunched or chewed as this interferes with the modified release of the 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.

4.3 Contraindications

• Hypersensitivity to the active substance, including drug-induced angioedema angio-oedema, or to any of the excipients listed in section 6.1.
• A history of orthostatic hypotension.
• Severe hepatic insufficiency.
• Tamsulosin should not be used concomitantly with potent CYP3A4 inhibitors such as ketoconazole (see section 4.5)

4.4 Special warnings and precautions for use

The ‘Intraoperative Floppy Iris Syndrome’ (IFIS, a variant of small pupil syndrome) has been observed during cataract or glaucoma surgery in some patients on or previously treated with tamsulosin hydrochloride. IFIS may increase the risk of 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 cataract or glaucoma 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, cataract 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 in patients with poor metaboliser CYP2D6 phenotype.

Tamsulosin hydrochloride should be used with caution in combination with strong and moderate inhibitors of CYP3A4 such as erythromycin (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 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 chlormadinone.

Diclofenac and warfarin may increase the elimination rate of tamsulosin.

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.

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 with another α1-adrenoreceptor antagonist can lead to hypotensive effects.

4.6 Fertility, pregnancy and lactation

Pregnancy and breast-feeding

Tamsulosin hydrochloride is not indicated for use in women.

Fertility

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 authorisation phase.”

	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)
Nervous system disorders	Dizziness (1.3%)	Headache	Syncope
Eye disorders					Blurred vision*,  Impaired vision*
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 disorders		Rash, Pruritus, Urticaria	Angioedema	Stevens-Johnson syndrome	Erythema multiforme*, Dermatitis exfoliative*
Reproductive system and breast disorders	Ejaculation disorders including Retrograde ejaculation, Ejaculation failure			Priapism
General disorders and administration site conditions		Asthenia

 * Observed in the post-marketing period

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 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

Symptoms

Overdosage with tamsulosin hydrochloride can potentially result in severe hypotensive effects. Severe hypotensive effects have been observed at different levels of overdosing. The largest dose of tamsulosin that was administered to an individual patient accidentally was 12 mg. The patient developed a headache, but did not require hospital treatment.

5.  PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in benign prostatic hypertrophy, alpha α1A adrenoreceptor antagonists. ATC code: G04CA02

Mechanism of action

Tamsulosin binds selectively and competitively to postsynaptic α1A adrenoreceptors, in particular to subtypes α 1A and α 1D, which convey smooth muscle contraction, thereby relaxing the prostatic and urethral smooth muscle.

Paediatric population
A double-blind, randomized randomised, 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 randomised 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 stabilisation 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 the same daily meal breakfast.

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.

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 sections 4.4 and 4.5).

The metabolites are not as effective and toxic as the active medicinal product itself.

6.  PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Content of capsule
Cellulose Microcrystalline microcrystalline cellulose
Methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 per cent
Polysorbate 80
Sodium laurilsulfate
Triethyl citrate
Talc

Capsule body shell
Gelatine
Indigotine Indigo carmine (E 132)
Titanium dioxide (E 171)
Yellow iron oxide (E 172)
Red iron oxide (E 172)
Black iron oxide (E 172)

6.3  Shelf life

36 months3 years.

6.4 Special precautions for storage

Blister packs: Store in the original package.
Tablet Capsule 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 capsule containers with PP child-resistant closures containing 10, 14, 20, 28, 30, 50, 56, 60, 90, 100, or 200 and multipacks containing 200 (2 packs of 100) modified-release capsules, hard.

HDPE capsule containers with PP child-resistant closures containing 10, 14, 20, 28, 30, 50, 56, 60, 90, 100 or 200 modified-release capsules.

Not all pack sizes may be marketed.

 

Section 1: Tamsulosin 400 micrograms Modified-Release Capsulesmodified-release capsules, hard.
Section 3: Orange/olive-green capsule, with the black printed mark ‘TSL 0.4’ and with a black stripe at both ends. The capsules contain white to off-white pellets.
Section 4.8: Reporting of suspected adverse reactions contact details updated for HPRA.
Section 6.1: Printing ink excipients deleted.

Ink

Shellac

Black iron oxide (E 172)
Propylene glycol

In section 4.8 (undesirable effects), dry mouth added. IMB fax number corrected.

Extensive updates in line with Core Safety Profile (NL/H/PSUR/0014/002).

4.2       Posology and method of administration

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

The safety and efficacy of tamsulosin in children < 18 years have not been established. Currently available data are described in section 5.1.

 

4.8       Undesirable effects
....
Cardiac disorders: Tachycardia Palpitations

 

5.1       Pharmacodynamic properties
....
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.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One capsule contains 400 micrograms of tamsulosin hydrochloride.
For a full list of excipients, see section 6.1.

4.2 Posology and method of administration

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.

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).

There is no relevant indication for use of Tamsulosin 0.4 mg capsules in children.

 

4.5 Interaction with other medicinal products and other forms of interaction

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, 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 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 α₁-adrenoreceptor antagonist may lower blood pressure.

 

4.9 Overdose

No cases of acute overdosage have been reported.However, acute hypotension could theoretically occur after overdosage in which case cardiovascular support should be given. 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

If large quantities of the medicinal product are involved, gastric lavage may be performed and activated charcoal and an osmotic laxative, such as sodium sulphate, may be given.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: α_1A adrenoreceptor antagonist, ATC code: G04CA02

4.5             Interaction with other medicinal products and other forms of interaction

No interactions have been observed when tamsulosin has been given concomitantly with atenolol, enalapril, nifedipine 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.

 

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 α1-adrenoreceptor antagonist may lower blood pressure.

4.8             Undesirable effects

	Common (>1/100, <1/10)	Uncommon (>1/1 000, <1/100)	Rare (>1/10 000, <1/1 000)	Very rare (<1/10 000)
Nervous system disorders	Dizziness	Headache	Syncope
Cardiac disorders		Tachycardia
Vascular disorders		Orthostatic hypotension
Respiratory, thoracic and mediastinum-related disorders		Rhinitis
Gastrointestinal disorders		Constipation, diarrhoea, nausea, vomiting
Skin and subcutaneous tissue disorders		Rash, itching, urticaria	Angio-oedema	Stevens-Johnson syndrome
Reproductive systems and breast disorders	Ejaculation disorders	Abnormal ejaculation		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 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.

Section 6.1: the capsule ink was updated to ' Shellac, Black iron oxide (E 172) and Propylene glycol'.

Section 6.3: the shelf-life was increased from 30 months to 36 months.