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Cardura XL (Doxazosin Mesylate) - Description and Clinical Pharmacology

 
 



CARDURA® XL
(doxazosin mesylate extended release tablets)

DESCRIPTION

CARDURAXL (doxazosin mesylate extended release tablets) contains doxazosin mesylate which is a quinazoline compound with the chemical name 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C23H25N5O5• CH4O3S and the molecular weight is 547.6. It has the following structure:

CARDURA XL is an extended release tablet for oral use and is designed to deliver 4 or 8 mg of doxazosin as the free base. Each 4 and 8 mg tablet contains 5.1 and 10.2 mg doxazosin mesylate (includes a 5% overage) to provide 4 and 8 mg doxazosin as a free base, respectively. The inactive ingredients for CARDURA XL are: polyethylene oxide, sodium chloride, hypromellose, red ferric oxide, titanium dioxide, magnesium stearate, cellulose acetate, Macrogol®, pharmaceutical glaze and black iron oxide.

CARDURA®XL System Components and Performance

CARDURA XL is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet.

The CARDURA XL utilizes GITS (Gastrointestinal Therapeutic System) which is designed to provide a controlled rate of delivery of doxazosin into the gastrointestinal lumen which is independent of pH or gastrointestinal (GI) motility. The function of CARDURA XL depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. The biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell.

CLINICAL PHARMACOLOGY

Mechanism of Action

The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy and incomplete emptying are related to two components, anatomical (static) and function (dynamic). The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha1 receptor decreases urethral resistance and may relieve the BPH symptoms and improve urine flow. Doxazosin mesylate is a selective inhibitor of the alpha1-subtype of alpha adrenergic receptors. In human prostate, doxazosin mesylate antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1A adrenoceptor.

Pharmacokinetics

The pharmacokinetics of CARDURA XL are different from those of doxazosin immediate-release (IR). CARDURA XL provides a controlled release of doxazosin over a 24-hour period.

Absorption

Pharmacokinetic parameters describing absorption following 4 and 8 mg Cardura XL daily doses are reported in Table 1 below. The relative bioavailability of CARDURA XL compared with doxazosin IR was 54% at the 4 mg dose and 59% for the 8 mg dose.

TABLE 1 Mean (±SD) Plasma Concentration of Doxazosin at Steady State in Healthy Volunteers: Pharmacokinetic Parameters
ParameterCARDURA XL
(4 mg)
CARDURA XL
(8 mg)
Cmax (ng/mL)10.1 ± 5.625.8 ± 12.1
AUC(0–∞)183 ± 85.5472 ± 170.8
Tmax (h)8 ± 3.79 ± 4.7

Effect of Food

As illustrated in Figure 1, the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) were approximately 32% and 18% higher, respectively, after CARDURA XL was administered in the fed state compared with the fasted state. In order to provide the most consistent exposure, CARDURA XL should be administered with breakfast. (See DOSAGE and ADMINISTRATION).

Effect of GI Retention Time

Markedly reduced GI retention times (e.g. short bowel syndrome) may influence the pharmacokinetics of CARDURA XL and possibly result in lower plasma concentrations. Conversely, markedly prolonged GI retention times (e.g. chronic constipation) can increase systemic exposure to doxazosin and potentially result in increased adverse reactions (See: PRECAUTIONS; General).

Distribution

At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.

Metabolism

Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP3A4; however, CYP2D6 and CYP2C19 metabolic pathways also exist to a lesser extent. No in vivo drug interaction studies have been performed with CARDURA XL. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. (See PRECAUTIONS; Drug Interactions).

Excretion

In a study of two subjects administered radiolabeled doxazosin IR 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average, only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. The apparent elimination half-life of CARDURA XL is 15–19 hours.

Pharmacokinetics in Special Populations

Age

The effects of age on the pharmacokinetics of CARDURA XL were examined. At steady state, increases of 27% in maximum plasma concentrations and 34% in the area under the concentration-time curve were seen in the elderly (>65 years old) compared to the young (See PRECAUTIONS; Geriatric Use).

Hepatic Impairment

Administration of a single 2 mg dose of doxazosin IR to patients with mild hepatic impairment (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin compared to patients without hepatic impairment. No studies have been performed to assess the effect of hepatic impairment on the pharmacokinetics of CARDURA XL. CARDURA XL should be administered with caution to patients with evidence of mild or moderately impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism. Use in patients with severe hepatic impairment is not recommended.

Drug-Drug Interactions

No in vivo drug-drug interaction studies have been performed to assess the effect of concomitant medications on the pharmacokinetics of CARDURA XL or to assess the effect of CARDURA XL on the pharmacokinetics of other drugs. In one placebo-controlled trial in normal volunteers, the administration of a single 1mg dose of doxazosin IR on day 1 of a four day regimen of cimetidine (400mg twice daily) resulted in a 10% increase in the mean AUC of doxazosin, 6% increase in mean Cmax of doxazosin and no significant change in mean half-life of doxazosin. Based upon the differences in dose and formulation, the applicability of these results to CARDURA XL is unknown. Otherwise, the interaction potential with other inhibitors or substrates of cytochrome P450 enzymes has not been determined. Pharmacodynamic interactions between CARDURA XL and anti-hypertensive medications or other vasodilating agents have also not been determined. Finally, drugs which reduce gastrointestinal motility leading to markedly prolonged GI retention times (e.g. anticholinergic agents) may increase systemic exposure to doxazosin.

Clinical Studies

Two controlled clinical studies were conducted with CARDURA XL in BPH patients, followed by an open-label extension study. Study 1 was a randomized, double-blind, parallel-group, placebo- and active-controlled study that compared the safety and efficacy of CARDURA XL (4 or 8 mg/day) with that of doxazosin IR (1, 2, 4, or 8 mg/day) and placebo over 13 weeks in 795 BPH patients, of whom 317 were randomized to CARDURA XL. Study 2 was a randomized, double-blind, parallel-group, active-controlled study that compared the safety and efficacy of CARDURA XL (4 or 8 mg/day) with that of doxazosin IR (1, 2, 4, or 8 mg/day) over 13 weeks in 680 BPH patients, of whom 350 were randomized to CARDURA XL.

In both studies, men aged 50–80 years with symptomatic benign prostatic hyperplasia (BPH) were enrolled. Symptomatic BPH was defined as a total score of at least 12 points on the 35-point International Prostate Symptom Score (IPSS) and a maximum urinary flow rate of ≤ 15mL/sec but no less than 5mL/sec (total voided volume ≥ 150mL). In these two studies, conducted in a total of 1475 patients, the mean age was 64 years (range 47–83 years). Patients were Caucasian (96%), Black (1.5%), Asian (1.5%), and of Other ethnicity (1%).

In both studies, CARDURA XL dosing was initiated after a 2 week placebo-run in period at 4 mg per day increasing to 8 mg per day after 7 weeks of treatment if adequate response (defined as having both an increase in maximum urinary flow rate of at least 3 ml/sec and a decrease in total I-PSS of at least 30% from baseline) was not seen. Doxazosin IR was titrated from an initial dose of 1 mg daily to 2 mg daily after 1 week with the option to increase to 4 mg daily after 3 weeks and then to a maximum of 8 mg daily after 7 weeks if an adequate response was not seen. The final daily dose of CARDURA XL was 4 mg in 43% of patients and was 8 mg in 57% of patients. The final daily dose of doxazosin IR was 1mg in 1%, 2mg in 12%, 4 mg in 30% of patients and 8 mg in 57% of patients.

There were two primary efficacy variables in each of these two controlled clinical studies: the International Prostate Symptom Score (I-PSS) and the peak urinary flow rate (Qmax). The I-PSS consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible total scores ranging from 0 to 35. The Qmax was measured in both studies just prior to the next dose. The results for total symptom score are given in Table 2, and for maximum urinary flow rate in Table 3.

TABLE 2 TOTAL INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS)Derived from IPSS questionnaire (range 0–35)
NMEAN BASELINE (±SD)MEAN CHANGE (±SE) 1
STUDY 1
Placebo15117.9 ± 4.3-6.1 ± 0.41
CARDURA XL31017.7 ± 4.3-8.0 ± 0.30 2
Doxazosin IR31117.8 ± 4.5-8.4 ± 0.29
STUDY 2
CARDURA XL33018.4 ± 5.0-8.1 ± 0.30
Doxazosin IR31318.4 ± 4.8-7.9 ± 0.31

1 Mean change from baseline to Week 13
2 Statistically significant difference (p <0.001) vs. placebo

TABLE 3 MAXIMUM FLOW RATE (mL/sec)
NMEAN BASELINE (±SD)MEAN CHANGE (±SE)Mean change from baseline to Week 13
STUDY 1
Placebo1519.8 ± 2.60.8 ± 0.32
CARDURA XL30010.3 ± 2.62.6 ± 0.24 1
Doxazosin IR30310.1 ± 2.72.2 ± 0.23
STUDY 2
CARDURA XL32210.5 ± 2.62.7 ± 0.27
Doxazosin IR31410.6 ± 2.62.7 ± 0.27
1 Statistically significant difference (p <0.001) vs. placebo

Mean changes in IPSS scores for CARDURA XL and placebo in Study 1 is summarized in Figure 2.

Mean changes in maximum urinary flow rate (Qmax) for both Cardura XL and placebo in Study 1 is summarized in Figures 3.

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