Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aventis Pharma Limited, One Onslow Street, Guildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Pharmacotherapeutic group: alpha-adrenoreceptor antagonists
ATC code: G04CA01
Alfuzosin is an orally active quinazoline derivative. It is a selective, peripherally acting antagonist of postsynaptic alpha-1-adrenoceptors.
In vitro pharmacological studies have documented the selectivity of alfuzosin for the alpha-1-adrenoreceptors located in the prostate, bladder base and prostatic urethra.
Clinical manifestations of Benign Prostatic Hypertrophy are associated with infra vesical obstruction which is triggered by both anatomical (static) and functional (dynamic) factors. The functional component of obstruction arises from the tension of prostatic smooth muscle which is mediated by alpha-adrenoceptors. Activation of alpha-1-adrenoceptors stimulates smooth muscle contraction, thereby increasing the tone of the prostate, prostatic capsule, prostatic urethra and bladder base, and, consequently, increasing the resistance to bladder outflow. This in turn leads to outflow obstruction and possible secondary bladder instability.
Alpha-blockade decreases infra vesical obstruction via a direct action on prostatic smooth muscle.
In vivo, animal studies have shown that alfuzosin decreases urethral pressure and therefore, resistance to urine flow during micturition. Moreover, alfuzosin inhibits the hypertonic response of the urethra more readily than that of vascular muscle and shows functional uroselectivity in conscious normotensive rats by decreasing urethral pressure at doses that do not affect blood pressure.
In man, alfuzosin improves voiding parameters by reducing urethral tone and bladder outlet resistance, and facilitates bladder emptying.
In placebo controlled studies in BPH patients, alfuzosin:
These favourable urodynamic effects lead to an improvement of lower urinary tract symptoms ie. filling (irritative) as well as voiding (obstructive) symptoms.
Alfuzosin may cause moderate antihypertensive effects.
A lower frequency of acute urinary retention is observed in the alfuzosin treated patient than in the untreated patient.
In the ALFAUR study, the effect of alfuzosin on the return of normal voiding was evaluated in 357 men over 50 years, presenting with a first episode of acute urinary retention (AUR), related to BPH. In this multicentre, randomised double blind parallel group study comparing alfuzosin 10mg/day and placebo, the evaluation of voiding was performed 24 hours after catheter removal, the morning after 2-3 days of treatment.
In men aged 65 years and over alfuzosin significantly increased the success rate of spontaneous voiding after catheter removal – see table. No benefit has been established in patients under 65 years of age or if treatment is extended beyond 4 days.
ALFAUR study: Percentage of patients (ITT population) successfully voiding post-catheter removal:
| Age | Placebo N (%) | Alfuzosin N (%) | Relative difference vs placebo 95%CI | p value |
|---|---|---|---|---|
| 65 years and above | 30 (35.7%) | 88 (56.1%) | 1.57 (1.14-2.16) | 0.003 |
| Below 65 years | 28 (75.7%) | 58 (73.4%) | 0.97 (0.77-1.22) | 0.80 |
| All patients (50 years and above) | 58 (47.8%) | 146 (61.9%) | 1.29 (1.04-1.60) | 0.012 |
Xatral XL is not indicated for use in the paediatric population (see section 4.2).
Efficacy of alfuzosin hydrochloride was not demonstrated in the two studies conducted in 197 patients 2 to 16 years of age with elevated detrusor leak point pressure (LPP≥40 cm H2O) of neurologic origin. Patients were treated with alfuzosin hydrochloride 0.1 mg/kg/day or 0.2 mg/kg day using adapted paediatric formulations).
The mean value of the relative bioavailability is 104.4% versus the immediate release formulation (2.5 mg tid) in middle-aged healthy volunteers and the maximum plasma concentration is being achieved 9 hours after administration compared to 1 hour for the immediate release formulation.
The apparent elimination half-life is 9.1 hours.
Studies have shown that consistent pharmacokinetic profiles are obtained when the product is administered after a meal.
Under fed conditions, mean Cmax and Ctrough values are 13.6 (SD=5.6) and 3.2 (SD=1.6) ng/ml respectively. Mean AUC0-24 is 194 (SD=75) ng.h/ml. A plateau of concentration is observed from 3 to 14 hours with concentrations above 8.1 ng/ml (Cav) for 11 hours.
Compared to healthy middle aged volunteers, the pharmacokinetic parameters (Cmax and AUC) are not increased in elderly patients.
Compared to subjects with normal renal function, mean Cmax and AUC values are moderately increased in patients with renal impairment, without modification of the apparent elimination half-life. This change in the pharmacokinetic profile is not considered clinically relevant. Therefore, this does not necessitate a dosing adjustment.
The binding of alfuzosin to plasma proteins is about 90%. Alfuzosin undergoes extensive metabolism by the liver, with only 11 % of the parent compound being excreted unchanged in the urine. The majority of the metabolites (which are inactive) are excreted in the faeces (75 to 91 %).
The pharmacokinetic profile of alfuzosin is not affected by chronic cardiac insufficiency.
CYP3A4 is the main hepatic enzyme isoform involved in the metabolism of alfuzosin (see section 4.5).
No data of therapeutic relevance.
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