- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Use during pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
1. Name of the medicinal product
Diffundox XL 400 microgram 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, hardOrange/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.
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 useOne 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).Paediatric PopulationThere is no relevant indication for use of tamsulosin hydrochloride in children.The safety and efficacy of tamsulosin in children <18 years have not been established. Currently available data are described in section 5.1
• Hypersensitivity to tamsulosin or any of the excipients.• Orthostatic hypotension observed earlier (history of orthostatic hypotension).• A history of tamsulosin induced angio-oedema.• Severe hepatic insufficiency.
4.4 Special warnings and precautions for use
The use of tamsulosin may lower blood pressure, which in rare cases may cause fainting. If initial symptoms of orthostatic hypotension start to appear (dizziness, weakness), then the patient should sit or lie down until the symptoms have gone. The patient should be examined before commencement of therapy with tamsulosin to exclude the presence of other conditions that can produce similar symptoms to those of BPH. The prostate should be examined via the rectum and, if necessary, the PSA count determined prior to commencement of treatment and again later at regular intervals. The treatment of severely renally impaired patients (creatinine clearance of < 10 ml/min) should be approached with caution as these patients have not been studied.Angio-oedema 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 lead to increased procedural complications during the operation. The initiation of therapy with tamsulosin in patients for whom cataract surgery is scheduled is not recommended.Discontinuing tamsulosin 1-2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of requirement of stopping the therapy prior to cataract surgery has not yet been established.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.
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 α1-adrenoreceptor antagonist may lower blood pressure.
4.6 Use during 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.
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||Palpitations, 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||Priapism|
|General disorders and administration site conditions||Asthenia|
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. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic groupTamsulosin is an α1A adrenoreceptor antagonist. The product is only used for the treatment of prostatic conditions. ATC code: G04CA02
Mechanism of actionTamsulosin binds selectively and competitively to postsynaptic α1A adrenoreceptors, which convey smooth muscle contraction by relaxing prostatic and urethral smooth muscle.
Pharmacodynamic effectsTamsulosin increases the maximum urinary flow rate by relaxing prostatic and urethral smooth muscle, thus relieving obstruction. The 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 product's effect on storage and voiding symptoms are also maintained during long-term therapy, as a result of which the need for surgical treatment is significantly postponed.
Paediatric populationA 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
AbsorptionTamsulosin 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.DistributionIn humans, tamsulosin is more than 99% bound to plasma proteins and the volume of distribution is small (about 0.2 l/kg).BiotransformationTamsulosin 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. ExcretionTamsulosin 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
Content of capsuleMicrocrystalline celluloseMethacrylic acid-ethyl acrylate copolymerPolysorbate 80Sodium laurilsulfateTriethyl citrateTalc
Capsule bodyGelatineIndigotine (E 132)Titanium dioxide (E 171)Yellow iron oxide (E 172)Red iron oxide (E 172)Black iron oxide (E 172)
InkShellacBlack iron oxide (E 172)Propylene Glycol Ammonium hydroxide (for pH-adjustment)
6.3 Shelf life
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 or 200 modified release capsules.Not all container sizes may be marketed..
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Winthrop Pharmaceuticals UK LimitedOne Onslow StreetGuildfordSurreyGU1 4YSUnited KingdomTrading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YSOrTrading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
03 February 2006
10. Date of revision of the text
One Onslow Street, Guildford, Surrey, GU1 4YS
+44 (0) 1483 554831
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