Diffundox

Diffundox XL 400 microgram Capsules

One capsule contains 400 micrograms tamsulosin hydrochloride.

For the full list of excipients, see section 6.1.

Modified-release capsule, hard

Hard gelatin capsules with orange coloured body and olive coloured cap. The capsule is filled with white to off-white pellets.

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

Oral use.

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 section 4.3).

Paediatric Population

There is no relevant indication for use of tamsulosin hydrochloride in children.

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

• Hypersensitivity to the active substance including drug-induced angioedema, or to any of the excipients listed in section 6.1.

• Orthostatic hypotension observed earlier (history of orthostatic hypotension).

• Severe hepatic insufficiency.

As with other α1 adrenoceptors antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin hydrochloride 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 hydrochloride 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.

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 hydrochloride. 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 yet 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 scheduled 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 (see section 4.5).

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 C_max 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 α₁adrenoreceptor antagonists could lead to hypotensive effects.

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.

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 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 of suspected adverse reactions

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 at: www.mhra.gov.uk/yellowcard.

Symptoms

Overdosage with tamsulosin hydrochloride 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 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.

Pharmacotherapeutic group: urologicals, alpha-adrenoreceptor antagonist;

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 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, as a result of which the need for surgical treatment is significantly postponed.

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.

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.

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

Gelatin

Indigotine (E132)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Not applicable.

36 months.

Blister packs: Store in the original package.

Capsule containers: Keep the container tightly closed.

PVC/PE/PVDC/Aluminium blister packs in cardboard boxes and 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.

No special requirements.

Zentiva Pharma UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

PL 17780/0233

03 February 2006 / 23 March 2010

29/08/2018