General
Prostate Cancer: 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.
Cataract Surgery: 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 of stopping alpha1
blocker therapy prior to cataract surgery.
Gastrointestinal Disorders: 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.
Patients with Hepatic Impairment: CARDURA XL should be administered with
caution to patients with evidence of mild or moderate hepatic dysfunction (see CLINICAL
PHARMACOLOGY; Pharmacokinetics in Special Populations). Since there is no
clinical experience in patients with severe hepatic dysfunction, use in these patients
is not recommended.
Drug Interactions: No in vivo drug interaction studies were conducted
with CARDURA XL (see CLINICAL PHARMACOLOGY; Drug-Drug Interactions). In vitro
studies suggest that doxazosin is a substrate of CYP3A4. Caution should be exercised
when concomitantly administering a potent 3A4 inhibitor, such as atanazavir, clarithromycin,
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin or voriconazole with CARDURA XL. Pharmacodynamic interactions between
CARDURA XL and anti-hypertensive medications or other vasodilating agents have also
not been determined.
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.
Information for Patients
Patients should be told about the possible occurrence of symptoms related to postural
hypotension, such as dizziness or syncope, when beginning therapy or when increasing
dosage strength of CARDURA XL. Patients should be cautioned about driving, operating
machinery, or performing hazardous tasks during this period, until the drug's
effect has been determined.
Patients should be informed that CARDURA XL extended release tablets should be swallowed
whole. Patients should not chew, divide, cut or crush tablets. Patients
should not be concerned if they occasionally notice in their stool something that
looks like a tablet. In the CARDURA XL extended release tablet, the medication is
contained within a nonabsorbable shell designed to release the drug at a controlled
rate. When this process is completed, the empty tablet is eliminated from the body.
CARDURA XL should be taken each day with breakfast.
Drug/Laboratory Test Interactions: Doxazosin mesylate does not affect the
plasma concentration of prostate specific antigen in patients treated for up to
3 years.
No clinically significant abnormalities in white blood cell (WBC) counts were reported
in patients treated with CARDURA XL in controlled clinical BPH trials. In previous
studies of doxazosin IR in BPH patients, the incidence of clinically significant
decreases in WBC counts was 0.4% in patients treated with doxazosin IR and 0% in
patients treated with placebo. There was no statistically significant difference
between these two groups.
Cardiac Toxicity in Animals: Studies in Sprague-Dawley rats after 6, 12,
and 18 months, and in CD-1 mice after 18 months of dietary administration showed
an increased incidence of myocardial necrosis or fibrosis at doxazosin base exposure
of 26-fold above the human exposure (AUC) at the maximum human recommended dose
(MHRD) of 8 mg of CARDURA XL. No cardiotoxicity was observed in dogs or Wistar rats
after 12 months of oral dosing at doxazosin base exposures of 65- and 85-fold, respectively,
above the human exposure (Cmax) at the MHRD of 8 mg of
CARDURA XL. There is no evidence that similar lesions occur in humans.
Carcinogenesis and Mutagenesis: Doxazosin mesylate was not carcinogenic to
rats or mice when administered daily for 2 years at doses up to 40 mg/kg/day or
120 mg/kg/day, respectively. Systemic drug exposures, as measured by AUC, were approximately
34-fold in rats and 16-fold in mice above the exposures at the MHRD of 8 mg CARDURA
XL.
Doxazosin base was not mutagenic in the in vitro bacterial Ames assays, the
chromosomal aberration assay in human lymphocytes, or the mouse lymphoma assay.
Doxazosin was not clastogenic in the in vivo mouse micronucleus assay. Doxazosin
mesylate has not been evaluated for genotoxicity.
Fertility in Males: Studies in rats after oral administration of doxazosin
base showed reduced fertility in males which was reversible after two weeks of treatment
termination at doxazosin base exposure of 13-fold above the human exposure (AUC)
at the MHRD of 8 mg of CARDURA XL. There have been no reports of any effects of
doxazosin on male fertility in humans.
Pregnancy: Teratogenic Effects, Pregnancy Category C. CARDURA XL is not indicated
for use in women.
There was no evidence of teratogenicity or embryotoxicity in rat or rabbit fetuses
that received up to 20 mg/kg/day or 41 mg/kg/day doxazosin base, respectively, administered
during major organ development. Plasma exposure at these doses is approximately
32- and 13-fold, respectively, above the AUC values for doxazosin base in humans
given the MHRD of 8 mg CARDURA XL. 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.
Because animal reproduction studies are not always predictive of human response,
CARDURA XL should be used during pregnancy only if clearly needed.
Doxazosin base was found to cross the placenta following oral administration to
pregnant rats, resulting in fetal exposure.
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 of CARDURA XL.
Nursing Mothers: CARDURA XL is not indicated for use in women.
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.
Pediatric Use: The safety and effectiveness of CARDURA XL in pediatric patients
have not been established.
Geriatric Use: 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 CLINICAL PHARMACOLOGY; Pharmacokinetics in Special Populations),
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 event 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%).