Doxazosin

7 DRUG INTERACTIONS • Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension. ( 7.1 ) • Concomitant administration of Doxazosin with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. ( 7.2 )

7.1 CYP 3A Inhibitors In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Strong CYP3A inhibitors may increase exposure to doxazosin. Monitor blood pressure and for symptoms of hypotension when Doxazosin is used concomitantly with strong CYP3A inhibitors [see Clinical Pharmacology (12.3) ].

7.2 Phosphodiesterase-5 (PDE-5) Inhibitors Concomitant administration of Doxazosin with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension. Monitor blood pressure and for symptoms of hypotension [see Warnings and Precautions (5.1) ]. Drug Interactions There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin (e.g., cimetidine).

Cimetidine: In healthy volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and a slight but not significant increase in mean C max and mean half-life of doxazosin. In vitro data in human plasma indicate that Doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.

8.1 Pregnancy Risk Summary The limited available data with Doxazosin in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. However, untreated hypertension during pregnancy can result in increased maternal risks [see Clinical Considerations ] . In animal reproduction studies, no adverse developmental effects were observed when doxazosin was orally administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 and 20 mg/kg, respectively (exposures in rabbits and rats were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose).

A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15‑20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Data Animal Data Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats. Studies in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations of 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of adverse developmental effects. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival.

In peri- and postnatal studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (about 8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes.