Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Zentiva Pharma UK Limited, One Onslow Street, Guildford, Surrey, GU1 4YS, United Kingdom Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Pharmacotherapeutic category: Adrenergic α1-receptors antagonist
ATC: G04CA02
The product is designed exclusively for the treatment of diseases of the prostate.
Tamsulosin binds selectively and competitively to post-synaptic α1-adrenoreceptors, prevailingly their subtypes designated α1A and α1D. Thus relaxation of smooth muscles of the prostate and urethra is achieved, which leads to a reduction of tonus and an improvement of the urinary flow.
Tamsulosin increases the maximum urinary flow. Due to relaxation of smooth muscles in the prostate and the urethra, obstruction is decreased, which leads to alleviation of voiding symptoms.
Tamsulosin also alleviates the storage symptoms in the development of which also the instability of the urinary bladder is involved at a significant extent. The effects on symptoms of filling and depletion of the urinary bladder persist during long-term treatment. The necessity of surgical treatment or catheterization is significantly delayed owing to these effects.
α1-blockers can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin in normotensive patients.
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.
Tamsulosin is absorbed from the intestinal tract and its bioavailability is almost complete. The absorption of tamsulosin decreases if the product is administered shortly after the meal. The uniformity of absorption may be supported via using the product tamsulosin capsules always after the same daily meal.
Kinetics of tamsulosin is linear.
After a single dose of tamsulosin taken after a full meal, the peak plasma levels are achieved at approximately 6 hours. The steady state is reached by day five of multiple dosing, when Cmax in patients is about two thirds higher than that reached after a single dose. Although this has been demonstrated only in the elderly, the same result would also be expected in younger patients.
There are huge inter-patient variations in plasma levels of tamsulosin, both after single as well as multiple dosing.
In humans, approximately 99% of tamsulosin is bound to plasma proteins and its distribution volume is small (approximately 0.2 l/kg).
Tamsulosin has a low first pass metabolic effect. The majority of tamsulosin is present in plasma in an unchanged form. Tamsulosin is metabolized in the liver.
In studies on rats, an induction of microsomal liver enzymes induced by tamsulosin has not been practically observed.
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 sections 4.4 and 4.5).
Dosage adjustment is not necessary in mild hepatic insufficiency.
The metabolites are not as effective and toxic as the active medicinal product itself.
Tamsulosin and its metabolites are mainly excreted in the urine; approximately 9% of the dose given is released in an unchanged form.
The elimination half-life of tamsulosin in patients is approximately 10 hours (when taken after a meal) and 13 hours in the steady state.
In case of renal affections, no reduction of tamsulosin doses is substantiated.
Toxicity after a single dose and multiple dosing has been investigated in mice, rats and dogs. Reproductive toxicity has also been investigated in rats, carcinogenicity in mice and rats, and genotoxicity in vivo and in vitro. The common toxicity profile with large doses of tamsulosin is equivalent to the pharmacological effect associated with alpha adrenergic antagonists.
Changes in ECG readings were found with very large doses in dogs. This is not, however, assumed to be of any clinical significance. Tamsulosin has not been found to have any significant genotoxic properties.
An increased incidence of proliferative alterations in the mammary glands of rat and mice females has been found. These findings, which are probably indirectly linked to hyperprolactinaemia and only occur as a result of large doses having been taken, are considered clinically insignificant.
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