Medicines Q&As
Q&A 22.5
What is the evidence comparing doxazosin XL with standard
doxazosin?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: November 2013
Background
Doxazosin XL is a controlled release gastrointestinal therapeutic system (GITS). The GITS
formulation was developed to enhance the pharmacokinetic profile allowing more uniform plasma
levels and eliminating at least two dose titration steps that may be needed with standard doxazosin,
whilst reducing the likelihood of significant first dose side effects (1).
The GITS formulation (Cardura XL) was originally licensed in the United Kingdom in 2001 for the
treatment of hypertension and benign prostatic hyperplasia (BPH).Since then it has come off patent
and is available as non-proprietary products.
The maximum licensed dose of Doxazosin XL tablets for hypertension and BPH is 8mg daily (2) , this
differs from that of standard tablets where the maximum dose for hypertension is 16mg per day (3).
Answer
Pharmacokinetic Comparisons
An open-label, randomised, crossover study to assess the pharmacokinetic characteristics of multiple
doses of the two doxazosin formulations in 31 healthy male volunteers was carried out by Chung et al
(1). The absorption of the GITS formulation was more gradual and more extended than that of the
standard formulation. The time to maximum concentration (t max) was longer with the GITS formulation
(8-9 hours) compared with that for the standard formulation (4 hours). The maximum plasma
concentration (Cmax) for the GITS formulation was lower than with the same dose of the standard
formulation. There was no significant difference in the minimum plasma concentrations (C min)
achieved by the two formulations. Plasma drug concentrations declined gradually with both
preparations (1)
Oral bioavailability of standard doxazosin is approximately 65% (1). Results of the multiple dose
crossover study demonstrated that doxazosin bioavailability from 4mg GITS and 8mg GITS was
54.1% and 58.6% respectively relative to standard doxazosin bioavailability.
The peak to trough blood level fluctuation of the GITS formulation was significantly lower and less
than half that of standard formulation doxazosin (1). The steady state concentration of GITS
remained more uniform, compared with that of the standard formulation.
Adverse effects Comparisons
A number of other clinical pharmacology studies in healthy subjects were also conducted (1). In total,
123 people received doxazosin GITS and 56 received standard doxazosin, ranging from single doses
to a maximum treatment period of 21 days. There were no serious adverse events reported and no
difference in type or incidence of adverse event reported between the two formulations.
A combined analysis of two randomised, double blind, parallel-group trials showed that the GITS
formulation provides equally effective blood pressure reduction compared with the standard
formulation (4). A total of 683 patients were included in the combined analysis. A gradual reduction
in blood pressure was seen with both formulations over a five-week period. Dose titration was not
Available through NICE Evidence Search at www.evidence.nhs.uk
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necessary with the GITS formulation because it did not produce the pronounced peak plasma
concentrations as seen with standard formulations. Fewer discontinuations and serious adverse side
effects were seen in the trials in patients taking the GITS formulation. From combined safety data,
5.3% of patients on doxazosin GITS and 9.3% on standard doxazosin withdrew because of adverse
events. Serious side effects were reported in 0.9% patients on GITS and 3.2% on standard
formulation; however no further details are provided about types of serious side effect or statistical
significance of these observations.
Hypertension
An open-label post marketing study evaluated the effectiveness and tolerability of replacing standard
doxazosin with the GITS formulation in hypertensive patients (n=3537) (5). The study had two
phases. During the first phase, of 3 – 6 months duration, patients were treated with standard
formulation doxazosin. Patients entering the second phase were then changed over to doxazosin
GITS formulation and treated for a further 3 months. The trial was powered so that an incidence of
syncope of 1.4% after changeover to the GITS formulation would be classed as statistically
significant. An incidence of this size is about double that seen in trials using standard doxazosin or
other antihypertensives. The design of this study did not allow for a direct comparison of the
effectiveness or tolerability of the two preparations, and those patients entering the second phase
were less likely to be susceptible to doxazosin toxicity. The changeover to the GITS formulation was
well tolerated with no reports of syncope. Also, the substitution had no negative impact on the
effectiveness of treatment of essential uncontrolled arterial hypertension.
A subsequent paper was later published based on a subgroup of patients aged 65 years and over
from the above study (6). The results from the study were similar to those stated above though again
the study design did not allow for a direct comparison of the two formulations. There was however a
significant rise in the degree of control achieved after standard doxazosin was replaced by the GITS
formulation in these patients. The authors concluded that switching from standard doxazosin to the
GITS formulation was not only safe but also enhanced the effectiveness of hypertension control.
A double-blind prospective randomised trial compared doxazosin GITS 4mg with doxazosin standard
2mg and 4mg in 310 hypertensive patients over a 9 week period. The study was conducted in two
phases. Phase I consisted of a 2 week placebo run-in and phase II consisted of 9 weeks of active
treatment (3 week fixed dose titration according to assigned treatment group and 6 week
maintenance therapy at the titrated dose; the GITS group received dummy titrations). Doxazosin
GITS was as effective as doxazosin standard in patients with mild to moderate hypertension in
decreasing systolic and diastolic blood pressure. Therapeutic equivalence between the 4mg
preparations was established at all visits. Doxazosin GITS and doxazosin 2mg standard both
produced significant decreases from baseline in diastolic and systolic blood pressures. The improved
pharmacokinetic profile of the GITS formulation compared with the standard formulation allowed a
therapeutic dose to be delivered earlier and without dose titration. Both formulations of doxazosin
were well tolerated (7).
In a multi-centre, prospective randomised study, the relative efficacy of doxazosin GITS versus
standard doxazosin on clinic and ambulatory blood pressure and serum lipids was compared in
patients with mild to moderate hypertension. Following a 2 week placebo run-in phase, 335 patients
were randomized to standard doxazosin 2 or 4 mg with dose titration or doxazosin GITS 4mg for 9
weeks. The active treatment phase consisted of a 3 week fixed dose titration schedule according to
assigned treatment group and a 6 week maintenance period at the titrated dose. Both formulations
were effective in reducing blood pressure without having a negative impact on serum lipids. Whilst
significantly more patients taking doxazosin GITS reached goal blood pressure (≤140/90mmHg)
compared with the doxazosin 2 mg group (p<0.0001), there was no significant difference in the
percentage of patients reaching goal blood pressure between the doxazosin GITS and standard
doxazosin 4 mg group. Doxazosin GITS was as effective as standard doxazosin 4mg in reducing
sitting blood pressure and superior to standard doxazosin 2mg (p> 0.0004). The GITS formulation
reduced the need for dose titration. Both doxazosin formulations were well tolerated (8).
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Benign Prostatic Hyperplasia (BPH)
Data was obtained from an integrated analysis of two multicentre studies which compared the efficacy
and tolerability of doxazosin GITS in BPH. The combined analysis aimed to validate the individual
study findings but with increased statistical power (9). Both studies included a 2-week washout period,
2-week single-blind placebo run-in phase and a 13-week double-blind treatment phase. Doxazosin
GITS was initiated at 4mg once daily and increased to 8mg once daily after 7 weeks, if indicated (n=
651 men). Standard doxazosin was initiated at 1mg once daily and titrated to 2mg after 1 week, to
4mg at 3 weeks and to 8mg at 7 weeks, if indicated to achieve symptom control (n= 640 men). It
should be noted that this titration regimen for standard doxazosin was more prolonged than
recommended in the Summary of Product Characteristics (SPC) for Cardura ® which allows as little as
3 weeks to reach 8mg from an initial dose of 1mg (3).
This integrated analysis found that both formulations significantly improved the symptoms of BPH and
produced clinically comparable improvements in maximum urinary flow rates, with greater
improvement observed earlier following treatment with doxazosin GITS than with standard doxazosin
(9). The overall incidence of adverse events (all causalities) was similar among patients treated with
doxazosin GITS and placebo, and higher among those on standard doxazosin (p<0.001). Adverse
events believed to be treatment related occurred in 16.1% of patients on doxazosin GITS, 25.3% of
patients on standard doxazosin, and 7.7% of patients on placebo (p value not stated). There was no
apparent difference in the type of adverse events reported for the two formulations.
A study was subsequently produced following on from the above integrated analysis to analyse the
effects of doxazosin GITS and standard doxazosin in BPH patients with regards to erectile
dysfunction (10). The trial was double blinded, placebo controlled and multicentre with a placebo run
in for 2 weeks prior to randomisation to active therapy: doxazosin GITS 4mg or 8mg daily (n=350) or
standard doxazosin 1-8mg daily (n=330) for 13 weeks. Of the 680 patients randomised into the study,
237 patients had erectile dysfunction at baseline. Patients made regular visits during the treatment
period to complete efficacy and adverse effects studies and, in addition, completed a questionnaire at
baseline and at the end of the study. A similar number of patients discontinued therapy in each group
due to treatment-emergent adverse effects (doxazosin GITS, n=21, 6.0%) and (standard doxazosin
n=16, 4.8%). An intention-to-treat analysis showed that whilst there were statistically significant
improvements in all five domains of the International Index of Erectile Function (IIEF) questions, there
were no differences between the two preparations overall.
A review of the current trial data with doxazosin standard and doxazosin GITS in BPH for their
tolerability and efficacy found that both doxazosin standard and GITS are well-tolerated and effective
therapies. They are not associated with worsening sexual dysfunction. Doxazosin GITS is better
tolerated because it minimizes fluctuations in serum concentration and possible adverse effects, such
as first dose effects (i.e. postural hypotension), that are observed with doxazosin standard (11).
Summary
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Both formulations provide effective blood pressure control.
Both formulations are effective in reducing the clinical symptoms of BPH and improving
maximum urinary flow rate.
The main advantage of the GITS formulation over the standard formulation is a smoother
plasma concentration profile, with smaller peak concentrations and less variation over 24
hours. This may be associated with fewer side effects in some patients.
There are fewer titration steps when using the GITS formulation than the standard
formulation and the GITS formulation allows a therapeutic dose to be delivered earlier
The maximum licensed dose of doxazosin GITS is 8mg per day for both hypertension and
BPH. Patients requiring more than 8mg doxazosin therefore need to remain on the
standard formulation doxazosin, which is licensed to a maximum of 16mg per day for
hypertension only.
Generic versions of the standard formulation are cheaper than the GITS formulation at the
time of writing (12).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Limitations
This Q&A does not include detailed cost comparisons.
See Q&A 101.1 (How should conversion between doxazosin formulations be carried out) for details
on how to switch between formulations.
Reference list
(1) Chung M, Vashi V, Puente J et al. Clinical pharmacokinetics of doxazosin in a controlledrelease gastrointestinal therapeutic system (GITS) formulation. Br J Clin Pharmacol 1999;
48:678-687.
(2) Summary of Product Characteristics. Cardura XL Pfizer Limited Accessed via:
www.emc.medicines.org.uk Date of access: 29/07/2013. Date of revision of the text: August
2012.
(3) Summary of Product Characteristics: Doxazosin Aurobindo Pharma-Milpharm ltd Accessed
via: www.emc.medicines.org.uk Date of access: 29/07/2013 Date of revision of the text:
April 2012.
(4) Os I, Stokke HP. Effects of doxazosin in the gastrointestinal therapeutic system formulation
versus doxazosin standard and placebo in mild-to-moderate hypertension. J Cardiovasc
Pharmacol 1999; 33:791-797.
(5) Anegon M, Esteban J, Jimenez-Garcia R et al. A postmarketing, open-label study to evaluate
the tolerability and effectiveness of replacing standard-formulation doxazosin with doxazosin
in the gastrointestinal therapeutic system formulation in adult patients with hypertension. Clin
Ther 2002; 24(5):786-797.
(6) Jimenez-Garcia R, Anegon M, Esteban J et al. Safety and effectiveness of replacing standard
doxazosin with doxazosin in the gastrointestinal therapeutic system (GITS) formulation in
elderly hypertensive patients. Int J Clin Pract 2003; 57(4):267-272.
(7) Os I. Comparison of doxazosin GITS and standard doxazosin in the treatment of high blood
pressure. Int J Clin Pharmacol Ther 2006; 44(3):99-106.
(8) Calvo C, Gil-Extremera B, Gomez-Fernandez P et al. Doxazosin GITS versus standard
doxazosin in mild to moderate hypertension. Int J Cardiol 2005; 101(1):97-104.
(9) Kirby R, Andersen M, Gratzke P et al. A combined analysis of double-blind trials of the
efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard
and placebo in patients with benign prostatic hyperplasia. BJU Int 2001; 87(3):192-200.
(10) Kirby R, O'Leary M, Carson C et al. Efficacy of extended-release doxazosin and doxazosin
standard in patients with concomitant benign prostatic hyperplasia and sexual dysfunction.
BJU Int 2005; 95:103-109.
(11) Fitzpatrick J, Desgrandchamps F. The clinical efficacy and tolerability of doxazosin standard
and gastrointestinal therapeutic system for benign prostatic hyperplasia. BJU Int 2005;
95:575-579.
(12) NHS Electronic Drug Tariff. August 2013. Prescription Pricing Authority 2005. Accessed via
http://www.ppa.org.uk/edt/November_2013/mindex.htm Date of access: 29-07-2013
Author
Lekha Shah, London Medicines Information Service (Northwick Park Hospital) (based on earlier work
by Alexandra Denby, Rebecca Willocks and Folake Kufeji)
Update Checked by
Varinder Rai, London Medicines Information Service (Northwick Park Hospital)
Contact
nwlh-tr.medinfo@nhs.net
Date Prepared
November 2013 (Update)
Date of check
November 2013
Available through NICE Evidence Search at www.evidence.nhs.uk
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Search strategy
 Embase - DOXAZOSIN/ct, cm, dt [Limit to: Publication Year 2008-Current] [ct=Clinical Trial,
cm=Drug Comparison, dt=Drug Therapy] AND GITS.ti,ab [Limit to: Publication Year 2008Current]
 Medline –DOXAZOSIN/ad, tu [Limit to: English Language and Humans and Publication Year
2008-Current] [ad=Administration & Dosage, tu=Therapeutic Use] AND GITS.ti,ab [Limit to:
Publication Year 2008-Current]
 SPC - Doxazosin and Cardura® XL
 Drug Tariff online
 NHS Evidence – Doxazosin and GITs
Available through NICE Evidence Search at www.evidence.nhs.uk
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