Diffundox™ XL 400 microgram Capsules

One capsule contains 400 micrograms of tamsulosin hydrochloride.

For excipients, see 6.1.

Modified release capsule, hard

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.

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

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.

• 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.

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.

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.

Tamsulosin is intended for males only.

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.

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).

No cases of acute overdosage have been reported. However, acute hypotension could theoretically occur after overdosage in which case 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.

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.

Pharmacotherapeutic group

Tamsulosin is an α_1A adrenoreceptor antagonist. The product is only used for the treatment of prostatic conditions.

ATC code: G04CA02

Mechanism of action

Tamsulosin binds selectively and competitively to postsynaptic α_1A adrenoreceptors, which convey smooth muscle contraction by 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 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.

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.

Excretion

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.

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.

Content of capsule

Microcrystalline cellulose

Methacrylic acid-ethyl acrylate copolymer

Polysorbate 80

Sodium laurilsulfate

Triethyl citrate

Talc

Capsule body

Gelatine

Indigotine (E 132)

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

Ink

Shellac

Black iron oxide (E 172)

Propylene Glycol

Not applicable.

36 months.

Blister packs: Store in the original package.

Tablet containers: Keep the container tightly closed.

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..

No special requirements.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

PL 17780/0233

03 February 2006

22 December 2006