TAMSULOSINE ZENTIVA LP 0,4 mg Cpr LP Plq/30

Each prolonged-release tablet contains 0.400 mg of tamsulosin hydrochloride, equivalent to 0,367 mg of tamsulosin.

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

Dosage

One tablet per day.

You may take tamsulosin regardless of food intake.

Renal impairment

No dose adjustment is necessary in cases of renal impairment.

Hepatic impairment

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

Paediatric population

No indication justifies the administration of tamsulosin in children.

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

Method of administration

Oral use.

The tablet must be swallowed whole, without being chewed or crushed, in order to ensure prolonged release of the active substance.

• Hypersensitivity to tamsulosin hydrochloride, including drug-induced angioedema, or to any of its excipients listed in section Composition ;
• History of orthostatic hypotension;
• Severe hepatic insufficiency.

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

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

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

"Intraoperative floppy iris syndrome" (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients treated or previously treated with tamsulosin. IFIS may increase technical difficulties during the procedure.

Discontinuing tamsulosine 1 to 2 weeks before cataract surgery may be considered useful. However, the benefit and the necessary duration of treatment interruption before surgery have not been established.

Initiating tamsulosine treatment is not recommended in patients scheduled for cataract or glaucoma surgery.

During the pre-operative consultation, surgeons and their team must check whether patients who are 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.

Tamsulosine must not be combined with potent CYP3A4 inhibitors in poor metabolisers with a CYP2D6 phenotype.

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

Tablet fragments may be observed in the stools.

Interaction studies have been conducted only in adults.

No interaction was observed when tamsulosine was administered concomitantly 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, nor do diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, simvastatin or warfarin alter the free fraction of tamsulosine in human plasma. Likewise, tamsulosine does not alter 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 tamsulosine hydrochloride by a factor of 2.8 and 2.2 respectively. Tamsulosine 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 of the AUC of tamsulosine by a factor of 1.3 and 1.6 respectively, but these increases are not considered clinically significant.

Concomitant administration with other α1-adrenoceptor antagonists may lead to hypotensive effects.

Tamsulosine is not indicated in women.

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.

No study has been carried out on the effects of tamsulosin on the ability to drive and use machines. However, patients should be warned that dizziness may occur.

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

Post-marketing experience:

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

Symptoms

An overdose of tamsulosin may potentially lead to severe hypotension. This severe hypotension has been observed at various levels of overdose.

Treatment

In the case of acute hypotension occurring after an overdose, cardiovascular support must be provided to the patient. 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 analeptic measures must be applied.

Dialysis cannot be of any help, as tamsulosin is strongly bound to plasma proteins.

Among the methods 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: medicines used in benign prostatic hyperplasia, alpha-adrenergic receptor antagonists; ATC code: G04CA02.

Mechanism of action

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

Pharmacodynamic Effects

Tamsulosin increases the maximum urinary flow rate. It relieves the obstruction by relaxing the smooth muscles of the prostate and urethra, and thereby improves the symptoms experienced during urination.

It also improves retention symptoms in which bladder instability plays an important role.

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

α1-adrenergic receptor antagonists may reduce blood pressure by decreasing peripheral resistance. However, no clinically significant decrease in blood pressure has been observed in studies of tamsulosin.

Paediatric population

A double-blind, randomised, placebo-controlled study covering a range of dosages was carried out in children with neuropathic bladder. A total of 161 children were randomised and treated with either one of the 3 dosages 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 a placebo. The primary criterion was: response by decrease of the "detrusor leak point pressure" (DLPP) (or LPP for leak point pressure) to a value <40 cm H2O, on two assessments performed on the same day. The secondary criteria were: the value and percentage change of detrusor leak point pressure from baseline, improvement or stabilisation of hydronephrosis and hydroureter, change in urine volume measured by catheterisation, and the number of times the protective pads were wet at the time of catheterisation, as recorded in the catheterisation diary. No statistically significant difference was found between the placebo group and any of the 3 tamsulosin dosage groups, either for the primary or the secondary criteria. Additional subgroup analyses confirmed these results (for example age, use of an anticholinergic, weight, geographic regions). No response was observed regardless of dosage.

Absorption

Tamsulosin in the form of prolonged-release capsules allows a prolonged release of tamsulosin and sufficient exposure over 24h with slight fluctuations. Tamsulosin administered in the form of prolonged-release capsules is absorbed in the intestine. It is estimated that, fasting, approximately 57 % of the administered dose is absorbed. The rate and extent of absorption of tamsulosin hydrochloride administered in the form of prolonged-release capsules are not affected by taking a low-fat meal. The absorption rate is increased by 64 % and 149 % (for AUC and Cmax) by taking a high-fat meal compared with fasting values.

The pharmacokinetics of tamsulosin are linear.

After administration of a single dose of tamsulosin prolonged-release capsule, the peak plasma concentration is reached on average 6 hours after intake. After repeated administrations, at plasma steady state which is reached on day 4, the maximum plasma concentration is reached between 4 and 6 hours, fasting or after a meal, respectively. Peak plasma concentrations reach 6 ng/ml at the first intake and up to 11 ng/ml at steady state.

Fasting, and after a meal, the minimum concentration of the prolonged form of tamsulosin represents 40 % of the maximum plasma concentration.

There is considerable inter-individual variation in the plasma concentrations reached, whether after a single dose or repeated doses.

Distribution

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

Biotransformation

The first-pass effect of tamsulosin hydrochloride is low; the molecule is present in large quantity 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 formed shows greater pharmacological activity than unchanged tamsulosin.

Elimination

Tamsulosin and its metabolites are mainly eliminated in the urine. Approximately 4 to 6% of the administered dose is excreted in unchanged form.

After administration of a single dose of 0,4 mg of tamsulosin in the form of a film-coated tablet, and at steady state, an elimination half-life of 19 hours and 15 hours, respectively, was measured.

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

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 was reported. These results, 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.

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree