Pharmacology Update

Azilsartan Medoxomil and Chlorthalidone (Edarbyclor®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A new angiotensin ii receptor blocker (ARB) and the thiazide diuretic, chlorthalidone, has been approved as a fixed combination for the treatment of hypertension. Azilsartan medoxomil, the prodrug of azilsartan, is a selective angiotensin II AT1 receptor antagonist. Chlorthalidone, a thiazide diuretic, has been in use for more than 50 years. The fixed combination is marketed by Takeda Pharmaceuticals America, Inc., as Edarbyclor.

Indications

The fixed combination of azilsartan/chlorthalidone (AZL/CT) is indicated for the treatment of hypertension in patients inadequately controlled with monotherapy.1

Dosage

The recommended starting dose is 40/12.5 mg once daily.1 The dose may be increased to 40/25 mg daily. The tablets may be taken without regard to meals.

AZL/CT is available as 40/12.5 and 40/25 mg.

Potential Advantages

Azilsartan 40 mg produces similar blood pressure reduction to maximum doses of olmesartan (40 mg) and valsartan (320 mg).2-4 The fixed combination of azilsartan and chlorthalidone produces a mean change in trough blood pressure (BP) of -24 to -30 (SBP) and -14 to -17 (DBP).4 AZL/CT 40/25 mg is statistically superior to olmesartan/HCTZ 40/25 mg.1

Potential Disadvantages

The incidence of dizziness was 8.9% compared to < 2% for monotherapy with each component.1 The frequency of study discontinuation was 8.3% for AZL/CT compared to 3.2% for each component. The most common reasons were increase in serum creatinine and dizziness. The frequencies of increase in serum creatinine of 30% or higher were approximately 8% for the fixed combination compared to approximately 2% for chlorthalidone monotherapy.5 This is a known pharmacologic effect of drugs targeting the renin-angiotensin aldosterone system.1

Comments

Azilsartan is similar to candesartan in terms of chemical structure as well as AT1 selectivity and receptor affinity. The antihypertensive effects of AZL/CT have been evaluated in five randomized controlled studies involving more than 3000 subjects administered AZL/CT and more than 2000 given an active comparator.1 In an 8-week trial, 1714 subjects were randomized to six combinations of AZL (20, 40, and 80 mg) and chlorthalidone (12.5 and 25 mg), as well as five arms of monotherapy for each drug. These subjects had mean baseline SBP of 165 mmHg and DBP of 95 mmHg. Change in BP was evaluated at trough (22-24 hours post dose) as well as clinic measured BP change. The fixed combination produced significant reduction in BP compared to each component alone. The effect was observed within 1 to 2 weeks. In a 12-week comparative study, AZL/CT 40/25 was found to be statistically superior to olmesartan/HCTZ (n = 719).1 In patients with baseline BP of 165/96 mmHg, clinic measured BP reductions were -43/-19 mmHg compared to -37/-16 mmHg. Based on clinical data, patients with a baseline blood pressure of 170/105 mmHg have an 85% chance of achieving BP < 140 SBP and < 90 DBP with AZL/CT 40/25 mg.1

Clinical Implications

Azilsartan is the eighth ARB to enter the market. The fixed combination appears to produce significant reduction in SBP and DBP. It may offer an option for patients with high baseline BP.

References

1. Edarbyclor Prescribing Information. Deerfield, IL: Takeda Pharmaceutical America, Inc; December 2011.

2. Edarbi Prescribing Information. Deerfield, IL: Takeda Pharmaceuticals America, Inc; November 2011.

3. White WB, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension 2011;57:413-420.

4. Sica D, et al. Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring. J Clin Hypertens 2011;13:467-472.

5. Zaiken K, et al. Azilsartan medoxomil: A new angiotensin receptor blocker. Clin Ther 2011;33:1577-1589.