when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3000 mg M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.
14 CLINICAL STUDIES
The antihypertensive effects of Edarbi have been demonstrated in a total of 7 double-blind, randomized studies, which included 5 placebo-controlled and 4 active comparator-controlled studies (not mutually exclusive). The studies ranged from 6 weeks to 6 months in duration, at doses ranging from 20 mg to 80 mg once daily. A total of 5941 patients (3672 given Edarbi, 801 given placebo, and 1468 given active comparator) with mild, moderate or severe hypertension were studied. Overall, 51% of patients were male and 26% were 65 years or older; 67% were white and 19% were black.
Two 6-week randomized, double blind studies compared the effect on blood pressure of Edarbi at doses of 40 mg and 80 mg, with placebo and with active comparators. Blood pressure reductions compared to placebo based on clinic blood pressure measurements at trough and 24 hour mean blood pressure by ambulatory blood pressure monitoring (ABPM) are shown in Table 1 for both studies. Edarbi, 80 mg, was statistically superior to placebo and active comparators for both clinic and 24 hour mean blood pressure measurements.
Table 1: Placebo Corrected Mean Change from Baseline in Systolic / Diastolic Blood Pressure at 6 Weeks (mm Hg) Study 1
N=1285 Study 2
N=989
Clinic Blood Pressure
(Mean Baseline
157.4 / 92.5) 24 Hour Mean by ABPM
(Mean Baseline
144.9 / 88.7) Clinic Blood Pressure
(Mean Baseline
159.0 / 91.8) 24 Hour Mean by ABPM
(Mean Baseline
146.2 / 87.6)
Edarbi 40 mg -14.6 / -6.2 -13.2 / -8.6 -12.4 / -7.1 -12.1 / -7.7
Edarbi 80 mg -14.9 / -7.5 -14.3 / -9.4 -15.5 / -8.6 -13.2 / -7.9
Olmesartan 40mg -11.4 / -5.3 -11.7 / -7.7 -12.8 / -7.1 -11.2 / -7.0
Valsartan 320 mg -9.5 / -4.4 -10.0 / -7.0
In a study comparing Edarbi to valsartan over 24 weeks, similar results were observed.
Most of the antihypertensive effect occurs within the first 2 weeks of dosing.
Figure 2 shows the 24-hour ambulatory systolic and diastolic blood pressure profiles at endpoint.
Figure 2: Mean Ambulatory Blood Pressure at 6 weeks by Dose and Hour
Other studies showed similar 24 hour ambulatory blood pressure profiles.
Edarbi has a sustained and consistent antihypertensive effect during long-term treatment, as shown in a study that randomized patients to placebo or continued Edarbi after 26 weeks. No rebound effect was observed following the abrupt cessation of Edarbi therapy.
Edarbi was effective in reducing blood pressure regardless of the age, gender, or race of patients, but the effect, as monotherapy, was smaller, approximately half, in black patients, who tend to have low renin levels. This has been generally true for other angiotensin II antagonists and ACE inhibitors.
Edarbi has about its usual blood pressure lowering effect size when added to a calcium channel blocker (amlodipine) or a thiazide-type diu |
