Edarbyclor is a combination of azilsartan medoxomil (angiotensin II receptor blocker; as its potassium salt) and chlorthalidone (thiazide-like diuretic). Azilsartan medoxomil, a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is an angiotensin II receptor blocker. Chlorthalidone is a monosulfamyl thiazide-like diuretic that differs chemically from thiazide diuretics by the lack of a benzothiadiazine structure. The potassium salt of azilsartan medoxomil, azilsartan kamedoxomil, is chemically described as (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1 H -benzimidazole-7-carboxylate monopotassium salt. Its empirical formula is C 30 H 23 KN 4 O 8. Chlorthalidone is chemically described as 2-chloro-5(1-hydroxy-3-oxo-1- isoindolinyl) benzenesulfonamide. Its empirical formula is C 14 H 11 ClN 2 O 4 S. The structural formula for azilsartan medoxomil is The structural formula for chlorthalidone is Azilsartan kamedoxomil is a white to nearly white powder with a molecular weight of 606.62. It is practically insoluble in water and freely soluble in methanol. Chlorthalidone is a white to yellowish white powder with a molecular weight of 338.76. Chlorthalidone is practically insoluble in water, in ether, and in chloroform; soluble in methanol; slightly soluble in ethanol. Edarbyclor is available for oral use as tablets. The tablets have a characteristic odor. Each Edarbyclor tablet contains 42.68 mg of azilsartan kamedoxomil, which is equivalent to containing azilsartan medoxomil 40 mg plus 12.5 or 25 mg of chlorthalidone. Each tablet of Edarbyclor also contains the following inactive ingredients: mannitol, microcrystalline cellulose, fumaric acid, sodium hydroxide, hydroxypropyl cellulose, crospovidone, magnesium stearate, hypromellose 2910, talc, titanium dioxide, ferric oxide red, polyethylene glycol 8000, and printing ink gray F1. Chemical Structure Chemical Structure

Edarbyclor is indicated for the treatment of hypertension, to lower blood pressure. Edarbyclor may be used in patients whose blood pressure is not adequately controlled on monotherapy. Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including thiazide-like diuretics such as chlorthalidone and ARBs such as azilsartan medoxomil. There are no controlled trials demonstrating risk reduction with Edarbyclor. 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. For specific advice on goals and management of high blood pressure, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg 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 is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients; however, the blood pressure effect of Edarbyclor in blacks is similar to that in non-blacks. Many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. The choice of Edarbyclor as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of Edarbyclor. Patients with moderate-to-severe hypertension are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, target goal and the incremental likelihood of achieving the goal with a combination product, such as Edarbyclor, versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient's risk. Data from an 8-week, active-controlled, factorial trial provide estimates of the probability of reaching a target blood pressure with Edarbyclor compared with azilsartan medoxomil or chlorthalidone monotherapy . Figures 1.a-1.d provide estimates of the likelihood of achieving target clinic systolic and diastolic blood pressure control with Edarbyclor 40/25 mg tablets after 8 weeks, based on baseline systolic or diastolic blood pressure. The curve for each treatment group was estimated by logistic regression modeling and is more variable at the tails. Figure 1.a Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8 Figure 1.b Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8 Figure 1.c Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8 Figure 1.d Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8 For example, a patient with a baseline blood pressure of 170/105 mm Hg has approximately a 48% likelihood of achieving a goal of <140 mm Hg (systolic) and 48% likelihood of achieving <90 mm Hg (diastolic) on azilsartan medoxomil 80 mg. The likelihood of achieving these same goals on chlorthalidone 25 mg is approximately 51% (systolic) and 40% (diastolic). These likelihoods rise to 85% (systolic) and 85% (diastolic) with Edarbyclor 40/25 mg. Edarbyclor is a combination of azilsartan medoxomil, an angiotensin II receptor blocker (ARB) and chlorthalidone, a thiazide-like diuretic combination product indicated for the treatment of hypertension, to lower blood pressure: In patients not adequately controlled with monotherapy As initial therapy in patients likely to need multiple drugs to help achieve blood pressure goals Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions Figure 1.a Figure 1.b Figure 1.c Figure 1.d

Edarbyclor is supplied in the following dosage strengths: 40/12.5 mg: pale red, round, biconvex, film-coated tablets, approximately 9.7 mm in diameter, with "A/C" and "40/12.5" imprinted on one side. Each tablet contains 40 mg of azilsartan medoxomil and 12.5 mg of chlorthalidone. 40/25 mg: light red, round, biconvex, film-coated tablets, approximately 9.7 mm in diameter, with "A/C" and "40/25" imprinted on one side. Each tablet contains 40 mg of azilsartan medoxomil and 25 mg of chlorthalidone. Tablets (azilsartan/chlorthalidone): 40/12.5 mg and 40/25 mg

Starting dose is 40/12.5 mg once daily Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on azilsartan medoxomil 80 mg or chlorthalidone 25 mg Dose may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals Maximal dose is 40/25 mg May be administered with other antihypertensive agents Edarbyclor may be administered with or without food Replace volume in volume-depleted patients prior to use 2.1 Dosing Information The recommended starting dose of Edarbyclor is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. The dosage may be increased to 40/25 mg after 2 to 4 weeks as needed to achieve blood pressure goals. Edarbyclor doses above 40/25 mg are probably not useful. Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of Edarbyclor. Edarbyclor may be administered with other antihypertensive agents as needed

Prior to Dosing Correct any volume depletion prior to administration of Edarbyclor, particularly in patients with impaired renal function or those treated with high doses of diuretics . Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to Edarbyclor, initially with a lower dose of chlorthalidone

Handling Instructions Do not repackage Edarbyclor. Dispense and store Edarbyclor in its original container to protect Edarbyclor from light and moisture.

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 In patients with renal artery stenosis, Edarbyclor may cause renal failure Monitor renal function in patients with renal impairment. Consider discontinuing Edarbyclor with progressive renal impairment Monitor serum electrolytes periodically 5.1 Fetal Toxicity Azilsartan medoxomil Edarbyclor can cause fetal harm when administered to a pregnant woman. 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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Edarbyclor as soon as possible . Chlorthalidone Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia

Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbyclor. Such patients are probably not good candidates to start therapy with more than one drug; therefore, correct volume prior to administration of Edarbyclor. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized

Impaired Renal Function Edarbyclor Monitor for worsening renal function in patients with renal impairment. Consider withholding or discontinuing Edarbyclor if progressive renal impairment becomes evident . Azilsartan medoxomil As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbyclor. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbyclor . In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results are expected. Chlorthalidone In patients with renal disease, chlorthalidone may precipitate azotemia. If progressive renal impairment becomes evident, as indicated by increased blood urea nitrogen, consider withholding or discontinuing diuretic therapy

Serum Electrolyte Imbalances Thiazide diuretics can cause hyponatremia and hypokalemia. Drugs that inhibit the renin angiotensin system can cause hyperkalemia. Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Co-administration of digitalis may exacerbate the adverse effects of hypokalemia. Monitor serum electrolytes periodically. Edarbyclor attenuates chlorthalidone-associated hypokalemia. In patients with normal potassium levels at baseline, 1.7% of Edarbyclor-treated patients, 0.9% of azilsartan medoxomil-treated patients, and 13.4% of chlorthalidone-treated patients shifted to low potassium values (less than 3.4 mmol/L)

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

Renal clearance of lithium is reduced by diuretics, such as chlorthalidone increasing the risk of lithium toxicity NSAIDS increase risk of renal dysfunction and interfere with antihypertensive effect Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia Lithium: Increases in serum lithium concentrations and lithium toxicity 7.1 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Edarbyclor and NSAID therapy. The antihypertensive effect of Edarbyclor may be attenuated by NSAIDs, including selective COX-2 inhibitors

Dual Blockade of the Renin-Angiotensin System (RAS) 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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Edarbyclor and other agents that affect the RAS. Do not coadminister aliskiren with Edarbyclor in patients with diabetes. Avoid use of aliskiren with Edarbyclor in patients with renal impairment (GFR <60 mL/min)

Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor agonists. Lithium renal clearance is reduced by diuretics, such as chlorthalidone. Monitor serum lithium levels during concomitant use.