Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group

α 1 -adrenoceptor antagonists.
ATC code: G04C A02. Preparations for the exclusive treatment of prostatic disease.

Mechanism of action
Tamsulosin binds selectively and competitively to the postsynaptic α 1 -adrenoceptors, in particular to subtypes α 1A and α 1D . It brings about relaxation of prostatic and urethral smooth muscle.

Pharmacodynamic effects

Omnic Ocas 0,4 increases the maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in prostate and urethra thereby improving voiding symptoms.
It also improves the storage symptoms in which bladder instability plays an important role.
These effects on storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterisation is significantly delayed.
α 1 -adrenoceptor antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with Omnic Ocas 0,4.

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

Omnic Ocas 0,4 is a prolonged release tablet of the non-ionic gel matrix type. The Ocas formulation provides slow release of tamsulosin, resulting in an adequate exposure over 24 hours, with little fluctuation.
Tamsulosin hydrochloride administered as prolonged release is absorbed from the intestine.
Under fasting conditions approximately 57% of the administered dose is estimated to be absorbed.
The rate and extent of absorption of tamsulosin hydrochloride administered as prolonged release tablets are not affected by a low fat meal. The extent of absorption is increased by 64% and 149% (AUC and C max respectively) by a high-fat meal compared to fasted.
Tamsulosin shows linear pharmacokinetics.
After a single dose of Omnic Ocas 0,4 in the fasted state, plasma concentrations of tamsulosin peak at a median time of 6 hours. In steady state, which is reached by day 4 of multiple dosing, plasma concentrations of tamsulosin peak at 4 to 6 hours, in the fasted and fed state. Peak plasma concentrations 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 Omnic Ocas 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. The volume of distribution is small (about 0.2 l/kg).

Biotransformation

Tamsulosin has a low first pass effect, being metabolised slowly. Most tamsulosin is present in plasma in the form of unchanged active substance. 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).
None of the metabolites is more active than the original compound.

Elimination

Tamsulosin and its metabolites are mainly excreted in the urine. The amount excreted as unchanged active substance is estimated to be about 4 - 6% of the dose, administered as Omnic Ocas 0,4.
After a single dose of Omnic Ocas 0,4 mg and in steady state, elimination half-lives of about 19 and 15 hours, respectively, have been measured.