TAMSULOSINE BIOGARAN LP 0,4 mg Gél LP Fl/30

Tamsulosin hydrochloride............................................................................................................................0.4 mg

For a prolonged-release capsule.

Treatment of the functional symptoms of benign prostatic hyperplasia.

One capsule per day, at a fixed time, preferably at the end of a substantial breakfast (or failing that, at the end of another meal).

The capsule must be swallowed with a glass of water without being chewed or crushed.

No dose adjustment is necessary in cases of renal insufficiency.

No dose adjustment is necessary in patients with mild to moderate hepatic insufficiency (see section Contraindications Contraindications

Paediatric population

The efficacy and safety of tamsulosin have not been established in children under 18 years of age. The data currently available are described in the section Pharmacodynamics.

This product must not be administered in the following situations:

• history of orthostatic hypotension;
• hypersensitivity to the active substance or to any of the excipients mentioned in section Composition ;
• history of angioedema with tamsulosin;
• severe hepatic impairment (class C of the CHILD-PUGH classification, which implies the simultaneous presence and marked expression of at least four of the following five signs: encephalopathy, ascites, hyperbilirubinemia, hypoalbuminemia, prolongation of prothrombin time; it indicates a high surgical risk during surgical treatment of portal hypertension).

This medicine is generally not recommended in cases of a history of micturition syncope.

Special warnings

Before starting treatment with TAMSULOSIN BIOGARAN L.P., the patient must be examined in order to exclude other causes responsible for the same symptoms as those of benign prostatic hyperplasia. A digital rectal examination and, if necessary, a prostate-specific antigen (PSA) assay must be performed before initiating treatment and then at regular intervals.

Risk of orthostatic hypotension :

In certain subjects, hypotension may occur on standing. Very rarely, it may lead to syncope. In the presence of prodromal symptoms (dizziness, fatigue, sweating), the patient should lie down until these symptoms have completely disappeared.

These phenomena, generally transient, occur at the start of treatment and do not prevent its continuation. The patient should be clearly informed of their occurrence.

Angioedema :

Skin or mucosal edema has been very rarely reported. In this case, TAMSULOSIN BIOGARAN LP must be stopped immediately and the patient treated and monitored until the edema disappears. Tamsulosin must not be re-prescribed to these patients.

Intraoperative floppy iris syndrome (IFIS) :

The "Intraoperative Floppy Iris Syndrome" (IFIS, a variant of the narrow pupil syndrome) has been observed during cataract and glaucoma surgery in some patients treated or previously treated with tamsulosin hydrochloride. IFIS may increase the risk of ocular complications during and after the operation.

Discontinuing tamsulosin hydrochloride 1 to 2 weeks before cataract or glaucoma surgery may be considered useful, but the benefit of discontinuing treatment has not been established. IFIS has also been reported in patients who had discontinued tamsulosin for a longer period before this surgery.

Initiation of treatment with tamsulosin hydrochloride in patients scheduled for cataract and glaucoma surgery is not recommended. During the pre-operative consultation, surgeons and their team 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 hydrochloride should not be combined with potent CYP3A4 inhibitors in poor metabolisers with a CYP2D6 phenotype.

Caution is advised when administering tamsulosin hydrochloride in combination with potent or moderate CYP3A4 inhibitors (see section Interactions).

Precautions for use

• Caution is required in subjects treated with antihypertensive medications, particularly calcium antagonists, which may cause severe hypotension.
  The resulting potentiation should be taken into account and the dosage of antihypertensives reduced accordingly;
• in coronary patients, specific treatment of coronary insufficiency may be continued; however, if angina recurs or worsens, treatment with tamsulosin should be discontinued;
• in patients with chronic renal failure, renal insufficiency leads to a moderate increase in blood levels without an increased incidence of adverse effects having been noted in clinical studies. It does not appear necessary to adjust the dosage of tamsulosin in subjects whose creatinine clearance is greater than 10 ml/min.
  On the other hand, caution is required in patients with severe renal failure (creatinine clearance < 10 ml/min) as these patients have not been studied;
• in elderly subjects over 65 years of age, the occurrence of orthostatic hypotension should be particularly taken into account.

Interaction studies have been conducted only in adults.

No interaction was observed when tamsulosin hydrochloride was co-administered with atenolol, enalapril or theophylline.

Concomitant intake of cimetidine increases plasma concentrations of tamsulosin; intake of furosemide decreases this concentration, however the concentrations remain within the dosage range, and no adjustment is necessary.

During tests in vitro, neither diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin nor warfarin modify the free fraction of tamsulosin in human plasma.

Likewise, tamsulosin does not modify the free fraction of diazepam, propranolol, trichlormethiazide and chlormadinone.

However, diclofenac and warfarin may increase the elimination of tamsulosin.

Concomitant administration of tamsulosine hydrochloride with strong CYP3A4 inhibitors may lead to an increase in exposure to tamsulosine hydrochloride. Concomitant administration with ketoconazole (known as a potent CYP3A4 inhibitor) resulted in an increase in the AUC and the Cmax of tamsulosin hydrochloride by a factor of 2,8 and 2,2 respectively. Tamsulosin hydrochloride must not be administered concomitantly with a potent CYP3A4 inhibitor in poor metabolisers with a CYP2D6 phenotype.

Tamsulosine hydrochloride should be used with caution in combination with moderate and potent CYP3A4 inhibitors.

Concomitant administration of tamsulosine hydrochloride with paroxetine, a potent CYP2D6 inhibitor, resulted in an increase in the Cmax and AUC of tamsulosine hydrochloride by a factor of 1,3 and 1,6 respectively, but these increases are not considered clinically significant.

Concomitant administration with other alpha1-blockers may cause hypotensive effects.

TAMSULOSINE BIOGARAN L.P. is not indicated in women.

The safety of tamsulosine hydrochloride during pregnancy and the passage of tamsulosine hydrochloride into breast milk are not known.

Fertility

Ejaculation disorders have been observed in short-term and long-term clinical studies with tamsulosine.

Ejaculation disorders, retrograde ejaculation and decreased or absent ejaculate have been reported following marketing.

Particular caution should be exercised by drivers of motor vehicles and users of machines due to the risk of orthostatic hypotension, especially at the start of treatment with tamsulosin.

The undesirable effects are classified by frequency as follows: Very common (≥1/10); common (≥1/100 <1/10); uncommon (≥1/1,000 <1/100); rare (≥1/10,000 <1/1,000); very rare (≥1/10,000), not determined (cannot be estimated from the available data).

The observed undesirable effects are listed in the following table:

* : Observed after marketing

Post-marketing experience:

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

In addition to the adverse events mentioned above, atrial fibrillation, arrhythmia, tachycardia and dyspnoea have been reported with the use of tamsulosin. As these events were reported spontaneously after worldwide marketing, their frequency and the role of tamsulosin in their occurrence cannot be determined.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Health care professionals should 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.ansm.sante.fr.

Overdose could lead to systemic hypotension.

In this case, place the patient in a supine position to restore blood pressure and normalise heart rate and, if necessary, implement monitoring of cardiovascular and renal parameters with restoration of blood volume and use of sympathomimetics.

In case of overdose, digestive absorption of the medicinal product may be reduced by induced vomiting, gastric lavage, use of activated charcoal and by an osmotic laxative such as sodium sulfate.

Dialysis, by contrast, appears unnecessary given the almost total binding of tamsulosin to plasma proteins.

Pharmacotherapeutic class: Alpha-blockers / Medicinal products used in benign prostatic hypertrophy, ATC code: G04CA02.

Mechanism of action

Tamsulosin is a selective post-synaptic α1-adrenergic receptor antagonist of α1A and α1D. These properties result in relaxation of the smooth muscle of the prostate and urethra.

Pharmacodynamic effects

Tamsulosin increases urinary flow and improves obstructive syndromes through relaxation exerted on prostatic and urethral smooth muscles.

The effects of tamsulosin on obstruction and micturition are maintained during long-term treatment.

Alpha1-blockers may cause a decrease in blood pressure through a mechanism of decreased peripheral vascular resistance. In clinical trials with tamsulosin, no clinically significant decrease in blood pressure has been reported.

Paediatric population

A randomised, double-blind, placebo-controlled, dose-finding study was conducted in children with neurogenic bladder. A total of 161 children (aged 2 to 16 years) were randomised and treated with either one of the 3 tamsulosin dose regimens (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 the number of patients who had a decrease in their "detrusor leak point pressure" (DLPP) to a value <40 cm of water, on two assessments performed on the same day. Secondary endpoints were: the value and percentage change in detrusor leak point pressure from baseline, improvement or stabilisation of hydronephrosis and hydroureter, the change in urine volume measured by catheterisation, and the number of times protective pads were wet at the time of catheterisation, as reported in the catheterisation diary. No statistically significant difference was found between the placebo group and any of the 3 tamsulosin dose groups, either for the primary endpoint or for the secondary endpoints. No response was observed regardless of the dose used (see section Dosage and administration).

The microgranules contained in the tamsulosin hydrochloride capsule release the active ingredient progressively and in a programmed manner.

This property makes it possible to maintain effective plasma levels in balance throughout the nycthemeron, thus allowing a single capsule to be taken every 24 hours.

Absorption

Tamsulosin hydrochloride is rapidly and completely absorbed (99 %) in the intestinal tract.

The bioavailability of tamsulosin hydrochloride is reduced at mealtimes, but can be made uniform by regular intake at the end of breakfast.

The pharmacokinetics of tamsulosin hydrochloride microgranules is linear.

After administration of a single dose at the time of a standard meal, the plasma peak (Cmax) is reached 6 hours after intake.

After repeated administrations, the plasma steady state is reached on day 5th day and the maximum concentration is approximately 2/3 higher than the initial maximum concentration.

There is a significant interindividual variation in the plasma concentrations reached, whether after a single dose or repeated doses; blood levels are generally below 20 ng/ml, but may sometimes exceed 30 ng/ml.

Distribution

In humans, tamsulosin hydrochloride is almost completely bound to plasma proteins and therefore has a low volume of distribution (approximately 0,2 L/kg).

Biotransformation

The first-pass effect of tamsulosin hydrochloride is low; the molecule is present in large quantities in plasma in unchanged form and is metabolised slowly in the liver.

In rats, practically no induction of hepatic microsomal enzymes related to tamsulosin was observed.

The results in vitro suggest that CYP3A4 and CYP2D6 are involved in the metabolism of tamsulosin hydrochloride, with a possible minor involvement of other CYP isoenzymes. Inhibition of the CYP3A4 and CYP2D6 enzymes responsible for drug metabolism could lead to an increase in exposure to tamsulosin hydrochloride (see sections Warnings and precautions and Interactions).

 None of the metabolites obtained is more active or more toxic than the parent molecule.

Elimination

Tamsulosin hydrochloride and its metabolites are mainly eliminated in the urine.

Approximately 9 % of the absorbed dose is excreted in unchanged form.

In patients, after a single tamsulosin capsule taken at a meal, on the one hand, and at plasma steady state, on the other hand, the elimination half-life is approximately 10 and 13 hours, respectively.

The terminal half-life, after a single tamsulosin capsule, is on average 22 hours.

Special populations

In elderly subjects, renally impaired patients (creatinine clearance >10 ml/min) and hepatically impaired patients (CHILD-PUGH class A and B), there is a moderate increase in blood levels of tamsulosin hydrochloride which does not justify dose adjustment. However, caution is required in this type of patient (see section Warnings and precautions Precautions for use

Acute toxicity tests allow an oral LD50 of approximately 700 mg/kg in rats and 1100 mg/kg in mice to be estimated.

The main risks of intoxication are of a neurovegetative nature:

• the doses without toxic effect in rats are:
  • 70 mg/kg/day for 3 months of treatment;
  • 5 mg/kg/day for 12 months of treatment;
• the target systems and organs are of 3 types:
  • purely pharmacological effects;
  • effects on the genital sphere;
  • functional hepatic effects;
• the genotoxicity tests were negative;
• the reproductive functions are not impaired;
• carcinogenicity studies show hyperplasia of the mammary glands related to the hyperprolactinemia induced by tamsulosin hydrochloride in rats.

For blister packs (PVC/PE/PVDC/Alu): 3 years.

For bottles (HDPE): 3 years.

For blister packs (PVC/PVDC/Alu): 1 year.

This medicine does not require any particular storage precautions.

No special requirements.

• Indication(s) listed in the marketing authorization on the date of publication of this order (Fl/30)