Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: KRKA, d.d., Novo mesto, ล marjeลกka cesta 6, 8501 Novo mesto, Slovenia
Pharmacotherapeutic group: Antihypertensives, alpha-adrenoceptor antagonists
ATC code: C02CA04
Doxazosin is a potent and selective post-junctional alpha1-adrenoceptor antagonist.
Administration of Doxazosin prolonged-release tablets to 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-adrenoreceptors 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. In patients with hypertension, blood pressure during treatment with Doxazosin prolonged-release tablets was similar in both the supine and standing position.
Responder data from the 2 primary hypertension efficacy studies (including a total of 630 doxazosin treated patients) indicate that those patients controlled on 1 mg, 2 mg or 4 mg doxazosin immediate release tablets would be equally well controlled on 4 mg Doxazosin prolonged-release tablets.
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with coexistent diabetes mellitus, gout and insulin resistance.
Doxazosin is suitable for use in patients with coexistent asthma, left ventricular hypertrophy and in elderly patients. Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation and enhanced activity of tissue plasminogen activator. Additionally, doxazosin improves insulin sensitivity in patients with impairment.
Doxazosin produces favourable effects on blood lipids, with a significant increase in the high-density lipoproteinHDL/total cholesterol ratio and trends to a favourable reduction in total triglycerides. It therefore confers an advantage over diuretics and beta adrenoceptor blocking agents which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favourable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in risk of developing coronary heart disease.
After oral administration of therapeutic doses, Doxazosin prolonged-release tablets are well absorbed with peak blood levels gradually reached at 8 to 9 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 characteristics of Doxazosin prolonged-release tablets will lead to a smoother plasma profile.
Peak/trough ratio of Doxazosin prolonged-release tablets is less than half that of immediate release Doxazosin tablets.
At steady-state, the relative bioavailability of doxazosin from Doxazosin prolonged-release tablets compared to the immediate release form was 54% at the 4 mg dose and 59% at the 8 mg dose.
Pharmacokinetic studies with Doxazosin prolonged-release tablets in the elderly have shown no significant alterations compared to younger patients.
The plasma elimination is biphasic with the terminal elimination half-life being 22 hours and hence this provides the basis for once daily dosing. Doxazosin is extensively metabolised with <5% excreted as unchanged drug.
Pharmacokinetic studies with immediate release 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 drugs known to influence hepatic metabolism (e.g. cimetidine). In a clinical study in 12 patients with moderate hepatic impairment, single dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 30%. (See section 4.4).
Approximately 98% of doxazosin is protein-bound in plasma.
Doxazosin is primarily metabolised by O-demethylation and hydroxylation.
Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent.
Preclinical data reveal no special hazard for humans based on conventional animal studies in safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. For further information see section 4.6 Pregnancy and lactation.
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