Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
Pharmacotherapeutic group: Alpha-adrenoceptor antagonists
ATC code: C02CA04
Administration of Raporsin XL, prolonged-release tablets in hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24-hours post dose. The majority of patients are controlled on the initial dose of 4 mg Raporsin XL, prolonged-release tablets. In patients with hypertension, the decrease in blood pressure during treatment with Raporsin XL, prolonged-release tablets was similar in both the sitting and standing position.
Patients treated with immediate release doxazosin tablets against hypertension can be transferred to Raporsin XL, prolonged-release tablets and the dose titrated upwards as needed, while maintaining effect and tolerability.
Habituation has not been observed during long-term treatment with doxazosin. Increase in plasma renin activity and tachycardia have rarely been seen during long-term treatment.
Doxazosin has a beneficial effect on blood lipids with significant increase of HDL/total cholesterol ratio (app. 4-13% of base line values), and significant reduction in total glycerides and total cholesterol. The clinical relevance of these findings is still unknown.
Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation as well as enhanced capacity of tissue plasminogen-activator. The clinical relevance of these findings is still uncertain. Additionally, doxazosin improves insulin sensitivity in patients with impaired sensitivity to insulin, but also concerning this finding the clinical relevance is still uncertain.
Doxazosin has shown to be free of metabolic adverse effects and is suitable for treatment of patients with coexistent asthma, diabetes, left ventricular dysfunction or gout.
Administration of Raporsin XL, prolonged-release tablets to patients with prostatic hyperplasia results in a significant improvement in urodynamics and symptoms as a result of a selective blockade of alpha-adrenoceptors located in the prostatic muscular stroma, capsule and bladder neck.
Most of the patients with prostatic hyperplasia are controlled with the initial dose.
Doxazosin has shown to be an effective blocker of 1A subtype of alpha-adrenoceptors which make up more than 70% of the adrenergic subtypes in prostate.
Throughout the recommended dosage range, Raporsin XL, prolonged-release tablets have only a minor or no effect on blood pressure in normotensive benign prostatic hyperplasia (BPH) patients.
After oral administration of therapeutic doses, doxazosin in Raporsin XL, prolonged-release tablets is well absorbed with peak blood levels gradually reached at 6 to 8 hours after dosing. Peak plasma levels are approximately one third of those of the same dose of immediate release doxazosin tablets. Trough levels at 24 hours are, however, similar. The pharmacokinetic properties of doxazosin in Raporsin XL, prolonged-release tablets lead to a minor variation in plasma levels. Peak/trough ratio of Raporsin XL, prolonged-release tablets is less than half that of immediate release doxazosin tablets.
At steady-state, the relative bioavailability of doxazosin from Raporsin XL, prolonged-release tablets compared to immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.
App. 98% of doxazosin is protein-bound in plasma.
Doxazosin is extensively metabolised with <5% excreted as unchanged product. Doxazosin is primarily metabolised by O-demethylation and hydroxylation.
The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basic for once daily dosing.
Pharmacokinetic studies with doxazosin in the elderly have shown no significant alterations compared to younger patients.
Pharmacokinetic studies with doxazosin in patients with renal impairment also showed no significant alterations compared to patients with normal renal function.
There are only limited data in patients with liver impairment and on the effects of medicinal products known to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase of AUC of 43% and a decrease in oral clearance of app. 40%. Doxazosin therapy in patients with hepatic impairment should be performed with caution (see section 4.4.).
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. Studies in pregnant rabbits and rats at daily doses resulting in plasma concentrations 4 and 10 times the human exposure (Cmax and AUC), respectively, revealed no evidence of harm to the foetus. A dosage regime of 82 mg/kg/day (8 times the human exposure) was associated with reduced foetal survival.
Studies in lactating rats given a single oral dose of radioactive doxazosin gave an accumulation in the breast milk with a maximum concentration of about 20 times greater than the maternal plasma concentration. Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
