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 MRHD 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 eva luated 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 MRHD 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 and thirty six patients treated with CARDURA XL (20% |
