Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha1-adrenoceptor antagonist.

ATC code: G04C A02. Preparations for the exclusive treatment of prostatic disease.

Mechanism of action:
Tamsulosin binds selectively and competitively to postsynaptic alpha1- receptors, in particular to the subtype alpha1A, which bring about relaxation of the smooth muscle of the prostate, whereby tension is reduced.
Pharmacodynamic effects:
Tamsulosin Inovamed increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction.

It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role. Alpha1-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with Tamsulosin Inovamed.

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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Tamsulosin Inovamed is formulated as a prolonged release tablet.
Tamsulosin hydrochloride administered as prolonged release tablets is absorbed from the intestine. Under fasting conditions approximately 57% of the administered dose is estimated to be absorbed. A consistent slow release of tamsulosin is maintained over the whole pH range encountered in the gastro-intestinal tract with little fluctuation over 24 hours. The extent of absorption is increased by 64% and 149% (AUC and Cmax respectively) by a high fat meal compared to fasted.

After a single dose of Tamsulosin Inovamed in the fasted state, plasma levels of tamsulosin peak at a median time of 6 hours. In steady state, which is reached by day 4 of multiple dosing, plasma levels of tamsulosin peak at 4 to 6 hours in the fasted and fed state. Peak plasma levels increase from approximately 6 ng/ml after the first dose to 11 ng/ml in steady state.

As a result of the prolonged release characteristics of Tamsulosin Inovamed, the trough concentration of tamsulosin in plasma amounts to 40% of the peak plasma concentration under fasted and fed conditions.
There is a considerable inter-patient variation in plasma levels, both after single and multiple dosing.

Distribution
In man, tamsulosin is about 99% bound to plasma proteins and volume of distribution is small (about 0.2 l/kg).

Metabolism
Tamsulosin has a low first pass effect, being metabolised slowly. Most tamsulosin is present in plasma in the form of unchanged drug. It is metabolised in the liver.

In rats, hardly any induction of microsomal liver enzymes was seen to be caused by tamsulosin.

In vitro results suggest that CYP3A4 and also CYP2D6 are involved in metabolism, with possible minor contributions to tamsulosin hydrochloride metabolism by other CYP isozymes. Inhibition of CYP3A4 and CYP2D6 drug metabolizing enzymes may lead to increased exposure to tamsulosin hydrochloride (see Section 4.4 and 4.5).

No dose adjustment is warranted in hepatic insufficiency.
None of the metabolites are more active than the original compound.

Elimination
Tamsulosin and its metabolites are mainly excreted in the urine. The amount excreted as unchanged drug is estimated to be about 4 - 6% of the dose, administered as Tamsulosin Inovamed.

After a single dose of Tamsulosin Inovamed, and in steady state, elimination half-lives of about 19 and 15 hours, respectively, have been measured.
No dose adjustment is necessary in patients with renal impairment.

Linearity/non-linearity
Tamsulosin shows linear kinetics.