WARNINGS AND PRECAUTIONS
Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of CARDURA XL. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing. As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. Care should be taken when CARDURA XL is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit from stopping alpha1 blocker therapy prior to cataract surgery.
As with any other non-deformable material, caution should be used when administering CARDURA XL to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable extended release formulation. Markedly increased GI retention times, as may occur in patients with chronic constipation, can increase systemic exposure to doxazosin and thereby potentially increase adverse reactions.
Carcinoma of the prostate causes many of the same symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with CARDURA XL.
Concomitant administration of CARDURA XL with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Pharmacodynamic interactions between CARDURA XL and antihypertensive medications or other vasodilating agents have not been determined.
Patients with Hepatic Impairment
CARDURA XL is not recommended for patients with severe hepatic impairment and should be administered with caution to patients with mild or moderate hepatic impairment [see
Use in Specific Populations, Clinical Pharmacology
Patients with Coronary Insufficiency
Patients with congestive heart failure, angina pectoris, or acute myocardial infarction within the last 6 months were excluded from the Phase 3 studies. If symptoms of angina pectoris should newly appear or worsen, CARDURA XL should be discontinued.
CYP 3A4 Inhibitors
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.
USE IN SPECIFIC POPULATIONS
Pregnancy Category C: CARDURA XL is not indicated for use in women. Doxazosin base was found to cross the placenta following oral administration to pregnant rats, resulting in fetal exposure. There was no evidence of teratogenicity or embryotoxicity in rat or rabbit fetuses at exposures 32- and 13- fold greater than the AUC values for doxazosin base in men given the maximum recommended human dose (MHRD) of 8 mg CARDURA XL. Maternal rat and rabbit doses were 20 mg/kg/day or 41 mg/kg/day doxazosin base, respectively, administered during major organ development. Embryolethality was observed in rabbits at a dose of 100 mg/kg/day of doxazosin mesylate when administered during major organ development. There are no adequate and well-controlled studies in pregnant women.
Nonteratogenic Effects: In pre- and postnatal development studies in rats, postnatal development was delayed, as evidenced by body weight gain suppression and a slight delay in the appearance of developmental anatomical landmarks and reflexes at a doxazosin base exposure of 26-fold above the human exposure (AUC) at the MHRD of 8 mg CARDURA XL.
Doxazosin base was secreted into the milk in lactating rats at concentrations approximately 20-fold above the exposure found in the maternal plasma following an oral dose of 1 mg/kg. It is not known if doxazosin is excreted in human breast milk. Use of CARDURA XL in nursing mothers is not recommended.
The safety and effectiveness of CARDURA XL in pediatric patients have not been established.
The incidence of hypotension with CARDURA XL use appears to be age related and more prevalent in patients 70 years or older. At steady state, increases of 27% in maximum plasma concentrations (Cmax) and 34% in the area under the concentration-time curve (AUC) were seen in the elderly (>65 years old) compared to the young [see
Of the 666 patients with BPH who received CARDURA XL in the two controlled clinical efficacy and safety studies, 325 patients (49%) were 65 years of age or older. One hundred thirty-six patients treated with CARDURA XL (20%) were >70 years of age.
In these two studies, the cumulative incidence of hypotension appeared to be age related. The reason for an increased incidence of hypotension in patients older than 70 years of age may be related to a modest increase in systemic exposure to doxazosin [see
], to an increased propensity to orthostasis in the elderly, or to an enhanced sensitivity to vasodilatory agents in the elderly. The incidence of hypotension reported as an adverse reaction was higher in patients 70 years of age and older (4/136; 2.9%) as compared to patients < 70 years of age (7/530; 1.3%).
Since there is no clinical experience in patients with severe hepatic impairment, use in these patients is not recommended. CARDURA XL should be administered with caution to patients with mild or moderate hepatic impairment [see
Warnings and Precautions, Clinical Pharmacology