A Pharmacist's Guide to Edarbyclor (azilsartan medoxomil and chlorthalidone)

This article is brought to you by Takeda Pharmaceuticals U.S.A., Inc.

By Jennifer Shannon, PharmD

Hypertension, or high blood pressure, is a serious condition that affects nearly 1 in 3 adults in the United States.¹ It may present without signs or symptoms, and therefore patients may not know they have the disease.² Sometimes, elevated blood pressure causes problems including heart attack or stroke.³ Pharmacists have a role in the management of this disease state, as we frequently encounter patients with hypertension who have questions about their condition, many of whom are on more than 1 medication.³ Patients whose hypertension remains inadequately controlled with monotherapy or who have a comorbid condition, such as diabetes, may need multiple medications to manage their blood pressure.³ Edarbyclor (azilsartan medoxomil and chlorthalidone), a combination medication indicated for the treatment of hypertension,⁴ has been available in the United States since the beginning of 2012. The goal of this guide is to aid pharmacists in answering questions patients may have if they are unfamiliar with this medication.

Question: What is Edarbyclor?

Answer: Edarbyclor is a once-daily, fixed-dose combination medication that combines an angiotensin II receptor blocker (ARB), azilsartan medoxomil, and a thiazide-like diuretic, chlorthalidone.⁴

The FDA approved Edarbyclor in December 2011 for the treatment of hypertension in patients whose blood pressure has not been adequately controlled with 1 medication or as an initial therapy for patients who are likely to need multiple drugs.^4,5 It is available in 40/12.5-mg and 40/25-mg fixed-dose combinations.⁴

Edarbyclor is the only hypertension therapy to combine an ARB with chlorthalidone,³ a diuretic that was approved in 1960.⁶

WARNING: FETAL TOXICITY

See full Prescribing Information for complete boxed warning.

• When pregnancy is detected, discontinue Edarbyclor as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Please see the Important Safety Information for Edarbyclor below.

Question: What studies have been conducted with Edarbyclor?

Answer: Several studies have demonstrated the antihypertensive effects of Edarbyclor in patients with moderate to severe hypertension, including 4 double-blind, randomized, active-controlled studies.⁴

In June 2012, Hypertension published results of a 12-week, randomized, double-blind, forced-titration, phase 3, active comparator study comparing a 40/25-mg fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide, marketed as Benicar HCT,³ with a 40/25-mg dose of azilsartan medoxomil and chlorthalidone.⁷ The study evaluated 1071 patients with mean baseline clinic systolic blood pressures (SBPs) ranging from 160 to 190 mm Hg.⁷ The primary end point was change from baseline in trough (24 hours postdose), seated, clinic SBP at week 12.⁷

Results after 12 weeks of treatment showed that the fixed-dose combination of azilsartan medoxomil and chlorthalidone 40/25 mg reduced clinic SBP by 43 mm Hg from baseline.⁴ The reductions were statistically significantly (P <.001) greater than that of the fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide 40/25 mg (37 mm Hg).⁴ Similar results were observed in all subgroups, including age, gender or race of patients.⁴

Question: What is chlorthalidone?

Answer: Chlorthalidone is a thiazide-like diuretic, a compound that causes the body to excrete water.⁴

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and heart attacks.⁴ There have been no trials of Edarbyclor showing reduced cardiovascular risk in patients with hypertension; however, trials with chlorthalidone and at least 1 drug pharmacologically similar to azilsartan medoxomil have demonstrated such benefits.⁴ Two landmark trials, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Systolic Hypertension in the Elderly Program (SHEP), showed that long-term use of chlorthalidone at doses of 12.5 mg to 25 mg were associated with reductions in risk of serious cardiovascular events, such as heart attack and stroke.^8,9

Question: Why should I care about lowering my high blood pressure?

Answer: Hypertension typically has no symptoms.² However, inadequately controlled hypertension may lead to serious cardiovascular events like heart attack and stroke.³

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mm Hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit also is greater for patients whose other health issues put them at higher risk of cardiovascular events, such as patients with diabetes.⁴

Question: What is the safety profile for Edarbyclor as a treatment for hypertension?

Answer: Edarbyclor has been evaluated for safety in more than 3900 patients with hypertension.⁴ Adverse events that occurred at an incidence of greater than or equal to 2% of Edarbyclor-treated patients and greater than azilsartan medoxomil or chlorthalidone were dizziness (8.9%) and fatigue (2.0%).⁴ Please see the following Important Safety Information for Edarbyclor.

Important Safety Information

WARNING: FETAL TOXICITY

See full Prescribing Information for complete boxed warning.

• When pregnancy is detected, discontinue Edarbyclor as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Edarbyclor is contraindicated in patients with anuria.

Do not coadminister aliskiren with Edarbyclor in patients with diabetes.

Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue Edarbyclor as soon as possible. Thiazides cross the placental barrier and appear in cord blood and may be associated with adverse reactions, including fetal or neonatal jaundice and thrombocytopenia.

In patients with an activated renin-angiotensin-aldosterone system (RAAS), such as volume- and/or salt-depleted patients, Edarbyclor can cause excessive hypotension. Correct volume or salt depletion prior to administration of Edarbyclor.

Monitor for worsening renal function in patients with renal impairment. In patients whose renal function may depend on the activity of the renin-angiotensin system, treatment with ACE inhibitors and ARBs has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. In patients with renal artery stenosis, Edarbyclor may cause renal failure. In patients with renal disease, chlorthalidone may precipitate azotemia. Consider withholding or discontinuing Edarbyclor if progressive renal impairment becomes evident. Avoid use of aliskiren with Edarbyclor in patients with renal impairment (GFR <60 mL/min).

Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Coadministration of digitalis may exacerbate the adverse effects of hypokalemia. Edarbyclor attenuates chlorthalidone-associated hypokalemia.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics.

Adverse Reactions (AEs):

• AEs that occurred at an incidence of ≥2% of Edarbyclor-treated patients and greater than azilsartan medoxomil or chlorthalidone were dizziness (8.9%) and fatigue (2.0%).

Incidence of consecutive elevations of creatinine (≥50% from baseline and >ULN) was 2% and were typically transient, or nonprogressive and reversible, and associated with large blood pressure reductions.

Drug Interactions:

• Renal clearance of lithium is reduced by diuretics, such as chlorthalidone, increasing the risk of lithium toxicity.
• Monitor renal function periodically in patients receiving Edarbyclor and NSAIDs who are also elderly, volume-depleted (including those on diuretics), or who have compromised renal function, as deterioration of renal function, including possible acute renal failure, may result. These effects are usually reversible. NSAIDs may interfere with antihypertensive effect.
• Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

For further information, please click here for complete Edarbyclor Prescribing Information.

Indications and Usage

Edarbyclor is an angiotensin II receptor blocker (ARB) and a thiazide-like diuretic combination product indicated for the treatment of hypertension to lower blood pressure. Edarbyclor may be used if a patient is not adequately controlled on monotherapy or as initial therapy if multiple drugs are needed to help achieve blood pressure goals. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. There are no controlled trials demonstrating risk reduction with Edarbyclor, but trials with chlorthalidone and at least one pharmacologically similar drug to azilsartan medoxomil have demonstrated such benefits.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals.

Edarbyclor may be used with other antihypertensive agents.

About the Author, Jennifer Shannon, PharmD

Dr Shannon is an assistant professor of pharmacy practice at the Philadelphia College of Osteopathic Medicine School of Pharmacy, where she facilitates lectures about cardiovascular disease. She also practices as a clinical pharmacist at the Good Samaritan Clinic in Gwinnett County, Georgia. Dr Shannon focuses her practice on disease management in core disease states, including hypertension, and has published numerous papers in a variety of pharmacy journals.

References

• Getting blood pressure under control. Centers for Disease Control and Prevention website. www.cdc.gov/VitalSigns/pdf/2012-09-vitalsigns.pdf. CDC Vitalsigns. Published September 2012. Accessed September 25, 2012.
• High blood pressure. Centers for Disease Control and Prevention website. www.cdc.gov/bloodpressure. Accessed December 11, 2012.
• Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252.
• Edarbyclor (azilsartan medoxomil and chlorthalidone) [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2012.
• Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. US Food and Drug Administration website. www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=202331&TABLE1=OB_Rx. Accessed December 11, 2012.
• Drugs@FDA: FDA approved drug products: Hygroton. US Food and Drug Administration website. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed December 19, 2012.
• Cushman WC, Bakris GL, White WB, et al. Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension. Hypertension. 2012;60(2):310-318.
• ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. JAMA. 2002;288(23):2981-2997.
• SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265(24):3255-3264.

Edarbyclor is a trademark of Takeda Pharmaceutical Company Limited registered with the US Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

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