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CARDURA® (XL) (doxazosin mesylate extended release tablets) Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 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 functional (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 the human prostate, doxazosin mesylate antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1A adrenoceptor.

12.2 Pharmacodynamics

Administration of CARDURA XL to patients with symptomatic BPH resulted in a statistically significant improvement in maximum urinary flow rate [see Clinical Studies (14.1)].

12.3 Pharmacokinetics

The pharmacokinetics of CARDURA XL is different from that of doxazosin 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 2 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 2 Mean (±SD) Plasma Concentration of Doxazosin at Steady State in Healthy Volunteers: Pharmacokinetic Parameters
Parameter CARDURA XL
(4 mg)
CARDURA XL
(8 mg)
Cmax (ng/mL) 10.1 ± 5.6 25.8 ± 12.1
AUC(0 – ∞) 183 ± 85.5 472 ± 170.8
Tmax (h) 8 ± 3.7 9 ± 4.7

Food Effect: As illustrated in Figure 1, the plasma Cmax and 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 (2.1)].

Figure 1

GI Retention Time Effect: 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 Warnings and Precautions (5.3)].

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 CYP 3A4; however, CYP 2D6 and CYP 2C9 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 has not been characterized [see Drug Interactions (7)].

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.

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 vitro studies suggest that doxazosin is a substrate of CYP 3A4. Caution should be exercised when concomitantly administering CARDURA XL with a strong CYP 3A4 inhibitor, such as atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole

In one placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin IR on day 1 of a four day regimen of cimetidine (400 mg twice daily) resulted in a 10% increase in the mean AUC of doxazosin, a 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 CYP 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.

Use in Specific Populations

Geriatric: In a study to assess the effect of age on the pharmacokinetics of CARDURA XL, increases of 27% in plasma Cmax and 34% in the plasma AUC were seen at steady state in the elderly (>65 years old) compared to the young [see Use in Specific Populations (8.5)].

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. Use in patients with severe hepatic impairment is not recommended. 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.

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