TAMSULOSINE BIOGARAN LP 0,4 mg Cpr LP Plq OPA/30

Tamsulosin hydrochloride........................................................................................................................0,400 mg

Equivalent to tamsulosin..............................................................................................................................0,367 mg

For a prolonged-release tablet

For the full list of excipients, see section Composition.

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

Dosage

One tablet per day.

Tamsulosin may be taken with or without food.

Renal impairment

No dose adjustment is justified in cases of renal impairment.

Hepatic impairment

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

Paediatric population

Tamsulosin is not indicated for use in children.

The safety and efficacy of tamsulosin in children and adolescents have not been established. The data currently available are described in the section Pharmacodynamics.

Method of administration

Oral use.

The tablet must be swallowed whole, without being crushed or chewed, as this interferes with the prolonged release of the active substance.

• Hypersensitivity to the active substance, including drug-induced angioedema, or to any of the excipients mentioned in the section Composition.
• History of orthostatic hypotension.
• Severe hepatic insufficiency.

As with other α1-adrenergic receptor antagonists, a drop in blood pressure may occur in a patient treated with tamsulosin; this may rarely manifest as syncope. At the first signs of orthostatic hypotension (dizziness, weakness), the patient must sit or lie down until the symptoms disappear.

Before starting any treatment with tamsulosin, the patient must be examined in order to rule out any other condition that may present with the same symptoms as benign prostatic hyperplasia. A rectal examination and, if necessary, a prostate-specific antigen (PSA) assay must be performed before starting treatment, and at regular intervals thereafter.

In patients with severe renal impairment (creatinine clearance < 10 mL/min), treatment will be initiated with caution, as these patients have not been the subject of specific studies.

The "intraoperative floppy iris syndrome" (IFIS, a variant of small pupil syndrome) has been observed during cataract and glaucoma surgery in some patients treated or previously treated with tamsulosin. IFIS may increase the risk of ocular complications during and after the surgical procedure.

Discontinuing tamsulosin 1 to 2 weeks before cataract or glaucoma surgery may be considered useful. However, the benefit of discontinuing treatment has not yet been established. Cases of IFIS have also been reported in patients who had discontinued tamsulosin longer before surgery.

Initiating treatment with tamsulosin is not recommended in patients who are scheduled to undergo cataract or glaucoma surgery.

During the pre-operative consultation, surgeons and ophthalmic teams should check whether patients who are going to undergo cataract or glaucoma surgery are or have been treated with tamsulosin, in order to ensure that appropriate measures will be put in place to manage the occurrence of IFIS during surgery.

Tamsulosin must not be combined with potent CYP3A4 inhibitors in patients with a CYP2D6 poor metabolizer phenotype.

Tamsulosin should be used with caution when combined with potent and moderate CYP3A4 inhibitors (see section Interactions).

Tablet fragments may be observed in the stools.

Interaction studies have only been performed in adults.

No interaction was observed when tamsulosin was administered concomitantly with atenolol, enalapril or theophylline.

Concomitant administration of cimetidine causes an increase in plasma levels of tamsulosin; furosemide, on the other hand, causes a decrease in this level. However, no dose adjustment is necessary as long as levels remain within the normal range.

In vitro, the free fraction of plasma tamsulosin is not modified by diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin and warfarin. Tamsulosin also does not modify the free fractions of diazepam, propranolol, trichlormethiazide and chlormadinone.

Diclofenac and warfarin may, however, increase the rate of elimination of tamsulosin.

Concomitant administration of tamsulosin hydrochloride and potent CYP3A4 inhibitors may result in increased exposure to tamsulosin hydrochloride. Concomitant administration of ketoconazole (a known potent 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 must not be combined with potent CYP3A4 inhibitors in patients with a CYP2D6 poor metabolizer phenotype.

Tamsulosin hydrochloride should be used with caution when combined with potent and moderate CYP3A4 inhibitors.

Concomitant administration of tamsulosin hydrochloride and paroxetine, a potent CYP2D6 inhibitor, resulted in increases in Cmax and AUC of tamsulosin by 1,3-fold and 1,6-fold respectively, but these increases were considered not clinically significant.

Simultaneous administration of other α1-adrenergic receptor antagonists may induce hypotensive effects.

Tamsulosin has no indication in women.

Ejaculation disorders have been observed in short- and long-term clinical studies with tamsulosin. Ejaculation disorders, retrograde ejaculation and anejaculation have been reported during the post-marketing period.

No studies have been conducted on the ability to drive vehicles and use machines. However, patients should be warned that dizziness may occur.

During cataract and glaucoma surgery, cases of narrow pupil, known as intraoperative floppy iris syndrome (IFIS), have been associated with tamsulosin treatment during post-marketing surveillance (see also section Warnings and precautions).

Post-marketing experience: in addition to the adverse events listed above, atrial fibrillation, arrhythmia, tachycardia and dyspnoea have been reported in association with the use of tamsulosin. Since these events are reported spontaneously during post-marketing experience worldwide, the frequency of these events and the role of tamsulosin in their occurrence cannot be determined with certainty.

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 national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website:www.signalement-sante.gouv.fr.

Symptoms

Overdose of tamsulosin may possibly induce severe hypotensive effects. Severe hypotensive effects have been observed at various degrees of overdose.

Treatment

In case of acute hypotension occurring after an overdose, cardiovascular support must be provided. Blood pressure and heart rate may be returned to normal by placing the patient in a supine position. If this measure is not sufficient, vascular filling and, if necessary, vasopressors must be used. Renal function must be monitored and general supportive measures must be applied.

Dialysis is unlikely to be useful because tamsulosin is very strongly bound to plasma proteins.

Among the measures used, emetics may hinder the absorption of tamsulosin. In the case of large quantities, gastric lavage may be undertaken; activated charcoal and an osmotic laxative, such as sodium sulfate, may be administered.

Pharmacotherapeutic class: Medicinal products used in benign prostatic hyperplasia, Alpha-blockers, ATC code: G04C A02.

Mechanism of action

Tamsulosin binds selectively and competitively to postsynaptic α1-adrenergic receptors, in particular to the α1A and α1D subtypes. It causes relaxation of prostatic and urethral smooth muscles.

Pharmacodynamic effects

Tamsulosin increases maximal urinary flow rate. It relieves obstruction by relaxing the smooth muscles of the prostate and urethra and, consequently, improves the symptoms experienced during micturition.

It also improves storage symptoms for which bladder instability plays an important role.

These effects on symptoms accompanying urinary retention and micturition are maintained during long-term treatment. Observational data indicate that the use of tamsulosin may delay the need for surgical intervention or catheterisation.

Alpha1-adrenergic receptor antagonists may reduce blood pressure by decreasing peripheral resistance. However, no clinically significant decrease in blood pressure has been observed in studies with tamsulosin.

Paediatric population

A double-blind, randomised, placebo-controlled, dose-finding study was conducted in children with neurogenic bladder. In total, 161 children were randomised and treated either with one of the 3 doses 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 with placebo. The primary endpoint was: the number of patients in whom the "detrusor leak point pressure" (DLPP) (or LPP for leak point pressure) had a value < 40 cm H2O, at two assessments performed on the same day. Secondary endpoints were: the value and percentage change of detrusor leak point pressure from baseline, improvement or stabilisation of hydronephrosis and ureterohydronephrosis, the change in urine volume measured by catheterisation, and the number of times protective pads were wet at the time of catheterisations, as indicated in the catheterisation diary. No statistically significant difference was detected between the placebo group and any of the 3 tamsulosin dose groups, either for the primary endpoint or for the secondary endpoints. Further exploratory analyses in subgroups confirmed these results (for example, age, anticholinergic use, weight, geographic regions). No response was observed regardless of dose.

Absorption

The prolonged-release formulation of tamsulosin ensures a slow release of tamsulosin, resulting in adequate exposure over 24 hours and low fluctuation.

Tamsulosin administered as prolonged-release tablets is absorbed in the intestine. It is estimated that approximately 57 % of the administered dose is absorbed.

The rate and extent of absorption of tamsulosin administered as prolonged-release tamsulosin hydrochloride tablets are not affected by food.

Tamsulosin has linear pharmacokinetics.

After a single dose of tamsulosin under fasting conditions, peak plasma concentrations of tamsulosin are reached at a median time of 6 hours. At steady state, which is reached on day 4e of multiple dosing, peak plasma concentrations of tamsulosin occur between the 4e and the 6e hour, whether the patient is fasting or not. Between the 1re dose and steady state, peak plasma concentrations change from 6 ng/mL to 11 ng/mL.

Due to the prolonged-release characteristics of prolonged-release tamsulosin tablets, the minimum plasma concentration of tamsulosin is equivalent to 40 % of the maximum plasma concentration, whether the patient is fasting or not.

There is considerable inter-individual variation in the plasma concentrations achieved, both after a single dose and after multiple doses.

Distribution

In humans, tamsulosin is 99 % bound to plasma proteins. The volume of distribution is low (approximately 0,2 L/kg).

Biotransformation

Being metabolised slowly, the first-pass effect of tamsulosin is weak. The major part of tamsulosin is present in plasma in the unchanged form of the active substance. It is metabolised in the liver.

In rats, only a very weak induction of hepatic microsomal enzymes is caused by tamsulosin.

None of the metabolites is more active than the original compound.

Elimination

Tamsulosin and its metabolites are eliminated essentially via the urine. The amount excreted as unchanged active substance is of the order of 4 to 6 % of the dose administered as prolonged-release tamsulosin capsules.

After a single dose of tamsulosin and during the steady-state phase, the elimination half-lives were measured at approximately 19 and 15 hours, respectively.

Single-dose and repeated-dose toxicity studies were carried out in mice, rats and dogs. Among others, reproductive toxicity in rats, carcinogenesis in mice and rats, and genotoxicity in vivo and in vitro were studied.

The general toxicity profile, as observed for high doses of tamsulosin, is consistent with the known pharmacological actions of alpha-adrenergic receptor antagonists.

At very high doses, the ECG is modified in dogs. This response is considered not clinically relevant. Tamsulosin does not possess significant genotoxic properties.

In female rats and mice, an increased incidence of changes in the mammary glands has been reported. These findings, probably resulting from hyperprolactinaemia and obtained only at very high doses, are not considered relevant.

3 years

Store in the original package, protected from light.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.