Takeda Pharmaceuticals America, Inc's Edarbi

Takeda Pharmaceuticals’ Edarbi (azilsartan medoxomil) is a new angiotensin receptor blocker (ARB) approved for use by the FDA on February 25, 2011.¹ ARBs inhibit the binding of angiotensin II, a naturally occurring hormone, to its receptors, resulting in a decrease in blood pressure. The FDA approved Edarbi for the treatment of hypertension in adults as monotherapy or in combination with other antihypertensive agents.¹

Pharmacology/ Pharmacokinetics

Edarbi is a prodrug that is hydrolyzed in the gastrointestinal tract to the active azilsartan. Azilsartan blocks the binding of angiotensin II at its receptors with a 10,000 times greater affinity for the AT 1 receptors over the AT2 . ² It is over 99% protein bound to albumin and is metabolized by the cytochrome P450 (CYP) system in the liver, specifically the CYP2C9 enzyme. Edarbi achieves peak plasma concentration within 1.5 to 3 hours and has a half-life of 11 hours with 60% bioavailability. ²

Clinical Trials

The efficacy and safety of azilsartan compared with olmesartan and valsartan was analyzed from a 6-week, randomized, double-blind, placebo-controlled study that enrolled 1291 men and women diagnosed with stages 1 and 2 hypertension. Subjects were assigned to receive a once-daily dose of azilsartan 20 or 40 mg, valsartan 160 mg, olmesartan 20 mg, or placebo.^2,3 After 2 weeks, subjects were titrated to azilsartan 80 mg, valsartan 320 mg, olmesartan 40 mg, or continued with placebo for 4 weeks. The primary efficacy end point was the change from baseline in 24-hour mean systolic blood pressure.

Edarbi 80 mg was superior at reducing 24-hour blood pressure when compared with other antihypertensives (valsartan and olmesartan); Edarbi 80 mg averaged -14.5/-8.4 mm Hg from baseline, olmesartan 40 mg averaged -11.8/-6.8 mm Hg from baseline, and valsartan 320 mg averaged -9.8/-5.7 mm Hg from baseline. Most of the Edarbi antihypertensive effect occurs in the first 2 weeks.²

Overall, the FDA approval of Edarbi was based on 7 double-blind randomized studies, of which 5 were placebo controlled and 4 were active comparator, enrolling a total of 5941 men and women randomized to receive Edarbi (3672), placebo (801), or an active comparator (1468).² All studies demonstrated consistent results.

Dosing/Precautions

The most common adverse events reported were diarrhea, nausea, and fatigue.^1,2 The most common adverse event leading to discontinuation of Edarbi was hypotension.² No rebound effect was observed following abrupt discontinuation. Just like other agents in the ARB II blocker class, Edarbi carries a boxed warning to avoid use in patients who are pregnant or breastfeeding. Agents with effects on the reninangiotensin system may damage the developing fetus in second and third trimester.

Angiotensin-converting enzyme inhibitor class agents lead to oliguria, progressive azotemia, and renal failure in patients with congestive heart failure or renal impairment. In patients with renal arterial stenosis, these agents can increase serum creatinine and blood urea nitrogen levels.² A study was conducted to evaluate the effects of 320 mg Edarbi on QT/QTc prolongation. The results showed no effects on QT/QTc prolongation. Serum creatinine increase is documented in patients younger than 75 years taking Edarbi.

Edarbi is taken once daily as an oral dose of 80 mg, with or without food. In an instance where a patient is on highdose diuretics, an adjusted or starting dose of 40 mg is recommended. There is no adjustment necessary for elderly patients, patients with renal impairment, and patients with mild hepatic dysfunction. Renal function should be monitored in patients with renal impairment and patients receiving Edarbi when taking nonsteroidal anti-inflammatory drugs.¹

Counsel patients to store Edarbi at room temperature (59°F-86°F) in the original container and to never transfer the drug to another container. Patients should also be reminded of the benefits of lifestyle modifications on high blood pressure. Edarbi is available in 40- and 80-mg unscored tablets. PT

Both Ms. Belisle and Dr. Patel are pharmacists at Brigham and Women’s Hospital, Boston, Massachusetts. Mr. White is a third-year PharmD candidate from Northeastern University School of Pharmacy currently on clinical cooperative rotation in the Investigational Drug Service at Brigham and Women’s Hospital, Boston, Massachusetts.

References

1. www.takeda.com/press/article_40273.html (accessed 3/22/2011)

2. Edarbi [package insert]. Deerfield, IL: Takeda Pharmaceuticals North America, Inc; 2011.

3. White WB, Weber MA, Sica D, 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(3):413-420.