Edarbyclor

Edarbyclor

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Contents
Azilsartan medoxomil, chlorthalidone.
Description
Each film-coated tablet contains azilsartan medoxomil 40 mg and chlorthalidone 12.5 or 25 mg.
Edarbyclor is a combination of azilsartan medoxomil (ARB; 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 a selective AT1 subtype angiotensin II receptor antagonist. 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}-1H-benzimidazole-7-carboxylate monopotassium salt. Its empirical formula is C30H23KN4O8.
Chlorthalidone is chemically described as 2-chloro-5(1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide. Its empirical formula is C14H11ClN2O4S.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: The active ingredients of Edarbyclor target two separate mechanisms involved in blood pressure regulation. Azilsartan blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells. Chlorthalidone produces diuresis with increased excretion of sodium and chloride at the cortical diluting segment on the ascending limb of henle's loop of the nephron.
Azilsartan Medoxomil: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principle pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Azilsartan blocks the vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.
An AT2 receptor is also found in many tissues, but the receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-agiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure.
Chlorthalidone: Chlorthalidone produces diuresis with increased excretion of sodium and chloride. The site of action appears to be the cortical diluting segment of the ascending limb of Henle's loop of the nephron. The diuretic effects of chlorthalidone lead to decreased extracellular fluid volume, plasma volume, cardiac output, total exchangeable sodium, glomerular filtration rate and renal plasma flow. Although the mechanism of action of chlorthalidone and related drugs is not wholly clear, sodium and water depletion appear to provide a basis for its antihypertensive effect.
Edarbyclor: Edarbyclor tablets have been shown to be effective in lowering blood pressure. Both azilsartan medoxomil and chlorthalidone lower blood pressure by reducing peripheral resistance but through complementary mechanisms.
Azilsartan Medoxomil: Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to azilsartan medoxomil 32 mg inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of azilsartan medoxomil to healthy subjects; no clinically significant effects on serum potassium or sodium were observed.
Chlorthalidone: The diuretic effect of chlorthalidone occurs in approximately 2.6 hrs and continues for up to 72 hours.
Clinical Studies: The antihypertensive effects of Edarbyclor have been demonstrated in a total of 5 randomized controlled studies, which included 4 double-blind, active-controlled studies and 1 open-label, long-term active-controlled study. The studies ranged from 8 weeks to 12 months in duration, at doses ranging from 20/12.5 mg to 80/25 mg once daily. A total of 5,310 patients (3,082 given Edarbyclor and 2,228 given active comparator) with moderate or severe hypertension were studied. Overall, randomized patients had a mean age of 57 years, and included 52% males, 72% whites, 21% blacks, 15% with diabetes, 70% with mild or moderate renal impairment, and a mean BMI of 31.6 kg/m2.
An 8-week, multi-center, randomized, double-blind, active-controlled, parallel group factorial trial in patients with moderate to severe hypertension compared the effect on blood pressure of Edarbyclor with the respective monotherapies. The trial randomized 1,714 patients with baseline systolic blood pressure between 160 and 190 mmHg (mean 165 mmHg) and a baseline diastolic blood pressure <119 mmHg (mean 95 mmHg) to one of the 11 active treatment arms.
The 6 treatment combinations of azilsartan medoxomil 20, 40 or 80 mg and chlorthalidone 12.5 or 25 mg resulted in statistically significant reduction in systolic and diastolic blood pressure as determined by ambulatory blood pressure monitoring (ABPM) (Table 1) and clinic measurement (Table 2) at trough compared with the respective individual monotherapies. The clinic blood pressure reductions appear larger than those observed with ABPM, because the former include a placebo effect, which was not directly measured. Most of the antihypertensive effect of Edarbyclor occurs within 1-2 weeks of dosing. The blood pressure lowering effect was maintained throughout the 24-hour period (see Tables 1, 2 and Figure 1).

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Edarbyclor was effective in reducing blood pressure regardless of age, gender, or race.
Edarbyclor was effective in treating black patients (usually a low-renin population).
In a 12-week, double-blind forced-titration trial, Edarbyclor 40/25 mg was statistically superior (P<0.001) to olmesartan medoxomil-hydrochlorothiazide (OLM/HCTZ) 40/25 mg in reducing systolic blood pressure in patients with moderate to severe hypertension (Table 3). Similar results were observed in all subgroups, including age, gender or race of patients. (See Table 3.)

Click on icon to see table/diagram/image

Edarbyclor lowered blood pressure more effectively than OLM/HCTZ at each hour of the 24-hour interdosing period as measured by ABPM.
Cardiovascular Outcomes: There are no trials of Edarbyclor demonstrating reductions in cardiovascular risk in patients with hypertension; however, trials with chlorthalidone and at least one drug pharmacologically similar to azilsartan medoxomil have demonstrated such benefits.
Pharmacokinetics: Edarbyclor: Following oral administration of Edarbyclor, peak plasma concentrations of azilsartan and chlorthalidone are reached at 3 and 1 hours, respectively. The rate (Cmax and Tmax) and extent (AUC) of absorption of azilsartan are similar when it is administered alone or with chlorthalidone. The extent (AUC) of absorption of chlorthalidone is similar when it is administered alone or with azilsartan medoxomil; however, the Cmax of chlorthalidone from Edarbyclor was 47% higher. The elimination half-lives of azilsartan and chlorthalidone are approximately 12 hours and 45 hours, respectively.
There is no clinically significant effect of food on the bioavailability of Edarbyclor.
Azilsartan Medoxomil: Absorption: Azilsartan medoxomil is rapidly hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.
The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentration (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.
Distribution: Azilsartan Medoxomil: The volume of distribution of azilsartan is approximately 16 L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein-binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.
In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.
Chlorthalidone: In whole blood, chlorthalidone is predominantly bound to erythrocyte carbonic anhydrase. In the plasma, approximately 75% of chlorthalidone is bound to plasma proteins, 58% of the drug being bound to albumin.
Metabolism and Elimination: Azilsartan Medoxomil: Azilsartan is metabolized to  two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of azilsartan medoxomil. The major enzyme responsible for azilsartan metabolism is CYP2C9.
Following an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.
Chlorthalidone: The major portion of the drug is excreted unchanged by the kidneys. Nonrenal routes of elimination have yet to be clarified. Data are not available regarding percentage of dose as unchanged drug and metabolites, concentration of the drug in body fluids, degree of uptake by a particular organ or in the fetus or passage across the blood-brain barrier.
Special Populations: Azilsartan Medoxomil: The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 2 as change relative to reference (test/reference). (See Figure 2.)

Click on icon to see table/diagram/image

Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of azilsartan medoxomil and chlorthalidone. However, these studies have been conducted for azilsartan medoxomil alone.
Azilsartan Medoxomil: Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (azilsartan medoxomil 450 mg/kg/day in the mouse and azilsartan medoxomil 600 mg/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, azilsartan medoxomil 80 mg/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested [approximately 8,000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1,000 mg M-II/kg/day (males) and up to 3,000 mg M-II/kg/day (females) in the rat] produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD.
Mutagenesis: Azilsartan medoxomil, azilsartan and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan, was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24-hr assay without metabolic activation.
Azilsartan medoxomil, azilsartan and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.
Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to azilsartan medoxomil 1,000 mg/kg/day [6,000 mg/m2 (approximately 122 times the MRHD of azilsartan medoxomil 80 mg/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3,000 mg M-II/kg/day.
Animal Toxicology and/or Pharmacology: Edarbyclor: The safety profiles of azilsartan medoxomil and chlorthalidone monotherapy have been individually established. To characterize the toxicological profile for Edarbyclor, a 13-week repeat-dose toxicity study was conducted in rats. The results of this study indicated that the combined administration of azilsartan medoxomil, M-II, and chlorthalidone resulted in increased exposures to chlorthalidone.
Pharmacologically-mediated toxicity, including suppression of body weight gain and decreased food consumption in male rats, and increases in blood urea nitrogen in both sexes, was enhanced by co-administration of azilsartan medoxomil, M-II, and chlorthalidone. With the exception of these findings, there were no toxicologically synergistic effects in this study.
In an embryofetal developmental study in rats, there was no teratogenicity or increase in fetal mortality in the litters of dams receiving azilsartan medoxomil, M-II and chlorthalidone concomitantly at maternally toxic doses.
Azilsartan Medoxomil: Reproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen 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 1,000 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 3,000 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.
Chlorthalidone: Reproductive Toxicology: Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus. Thiazides cross the placental barrier and appear in cord blood.
Pharmacology: Biochemical studies in animals have suggested reasons for the prolonged effect of chlorthalidone. Absorption from the gastrointestinal tract is slow because of its low solubility. After passage to the liver, some of the drug enters the general circulation, while some is excreted in the bile, to be reabsorbed later. In the general circulation, it is distributed widely to the tissue, but is taken up in highest concentrations by the kidneys, where amounts have been found 72 hrs after ingestion, long after it has disappeared from other tissues. The drug is excreted unchanged in the urine.
Indications/Uses
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: 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. 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 nonblacks. Many antihypertensive drugs have additional approved indications and effects (eg, 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 (eg, 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 (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Figures 3a-3d 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. (See Figures 3a, 3b, 3c and 3d.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

For example, a patient with a baseline blood pressure of 170/105 mmHg has approximately a 48% likelihood of achieving a goal of <140 mmHg (systolic) and 48% likelihood of achieving <90 mmHg (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.
Dosage/Direction for Use
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.
Edarbyclor may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic/diastolic clinic blood pressure reduction of 13/6 mmHg when switched to Edarbyclor 40/12.5 mg. Patients not controlled with chlorthalidone 25 mg may have an additional clinic blood pressure reduction of 10/7 mmHg when switched to Edarbyclor 40/12.5 mg.
Edarbyclor may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.
Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of Edarbyclor.
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 (see Precautions).
Patients who experience dose-limiting adverse reactions on chlorthalidone may be switched to Edarbyclor, initially with a lower dose of chlorthalidone (see Precautions).
Administration: Edarbyclor may be taken with or without food (see Pharmacology under Actions).
Edarbyclor may be administered with other antihypertensive agents as needed.
Overdosage
Limited data are available related to overdosage in humans.
Azilsartan Medoxomil: Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to azilsartan medoxomil 320 mg were administered for 7 days and were well-tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patient's clinical status. Azilsartan is not dialyzable.
Chlorthalidone: Symptoms of acute overdosage include nausea, weakness, dizziness and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.
Contraindications
Edarbyclor is contraindicated in patients with anuria (see Precautions).
Patients with hypersensitivity to any component of edarbyclor tablet contraindicated from being administered any component of medication.
Do not administer aliskerin with Edarbyclor in patients with diabetes (see Interactions).
Use in Pregnancy: Pregnancy is also contraindicated in use of this drug judging from the clinical experience of angiotensin converting enzyme inhibitors and findings derived from toxicological studies of azilsartan medoxomil.
Special Precautions
Fetal Toxicity: Azilsartan Medoxomil: 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 (see Use in Pregnancy and Lactation).
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 (eg, 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.
When Edarbyclor is used in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered. In these patients Edarbyclor should be carefully titrated with thorough monitoring of blood pressure.
Evaluation of patients with heart failure should include periodic assessments of renal function. During those titration of Edarbyclor, monitoring of serum creatinine and potassium is recommended. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.
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 (eg, 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 acute hypotension, oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbyclor (see Pharmacology under Actions, Use in Pregnancy and Lactation and Interactions).
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.
Hypokalemia: Chlorthalidone: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Co-administration of digitalis may exacerbate the adverse effects of hypokalemia.
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 Artery Stenosis: Azilsartan Medoxomil: Other drugs that affect the renin-angiotensin-aldosterone system, ie, angiotensin converting enzyme inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. There has been no long-term use of azilsartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Hepatic Impairment: Chlorthalidone: Chlorthalidone should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with azilsartan medoxomil/chlorthalidone in patients with hepatic impairment.
Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Azilsartan Medoxomil: No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Azilsartan medoxomil has not been studied in patients with severe hepatic impairment (see Pharmacology: Pharmacodynamics under Actions).
Renal Impairment: Edarbyclor: Safety and effectiveness of Edarbyclor in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) have not been established. No dose adjustment is required in patients with mild (eGFR 60-90 mL/min/1.73 m2) or moderate (eGFR 30-60 mL/min/1.73 m2) renal impairment.
Chlorthalidone: Chlorthalidone may precipitate azotemia.
Use in Children: Safety and effectiveness of Edarbyclor in pediatric patients under 18 years of age have not been established. Neonates with a history of in utero exposure to Edarbyclor: If oliguria or hypotension occurs, support blood pressure and renal function. Exchange transfusions or dialysis may be required.
Use in the Elderly: Edarbyclor: No dose adjustment with Edarbyclor is necessary in elderly patients. Of the total patients in clinical studies with Edarbyclor, 24% were elderly (≥65 years); 5.7% were ≥75 years. No overall differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see Pharmacology under Actions).
Use In Pregnancy & Lactation
Use in Pregnancy: In the US, Pregnancy Category D.
Use of drugs that affect 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. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Edarbyclor, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Edarbyclor for hypotension, oliguria and hyperkalemia.
Use in Lactation: It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats and thiazide-like diuretics like chlorthalidone are excreted in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
The following potential adverse reactions with Edarbyclor, azilsartan medoxomil or chlorthalidone and similar agents are included in more detail in the Precautions section of the label:  Fetal toxicity; hypotension in volume- or salt-depleted patients; impaired renal function; hypokalemia; hyperuricemia.
Clinical Trials Experience:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Edarbyclor has been evaluated for safety in  more than 3,900 patients with hypertension; more than 700 patients were treated for at least 6 months and more than 280 for at least 1 year. Adverse reactions have generally been mild and transient in nature.
Common adverse reactions that occurred in the 8-week factorial design trial in at least 2% of Edarbyclor-treated patients and greater than azilsartan medoxomil or chlorthalidone are presented in Table 4 (See Table 4.)

Click on icon to see table/diagram/image

Hypotension and syncope were reported in 1.7% and 0.3%, respectively, of patients treated with Edarbyclor.
Study discontinuation because of adverse reactions occurred in 8.3% of patients treated with the recommended doses of Edarbyclor compared with 3.2% of patients treated with azilsartan medoxomil and 3.2% of patients treated with chlorthalidone. The most common reasons for discontinuation of therapy with Edarbyclor were increased serum creatinine (3.6%) and dizziness (2.3%).
The adverse reaction profile obtained from 52 weeks of open-label combination therapy with azilsartan medoxomil plus chlorthalidone or Edarbyclor was similar to that observed during the double-blind, active controlled trials.
In 3 double-blind, active controlled, titration studies, in which Edarbyclor was titrated to higher doses in a step-wise manner, adverse reactions and discontinuations for adverse events were less frequent than in the fixed-dose factorial trial.
Azilsartan Medoxomil: A total of 4,814 patients were evaluated for safety when treated with azilsartan medoxomil at doses of 20, 40 or 80 mg in clinical trials. This includes 1,704 patients treated for at least 6 months, of these, 588 were treated for at least 1 year. Generally, adverse reactions were mild, not dose-related and similar regardless of age, gender and race.
Adverse reactions with a plausible relationship to treatment that have been reported with an incidence of ≥0.3% and greater than placebo in more than 3,300 patients treated with azilsartan medoxomil in controlled trials are listed as follows: Gastrointestinal Disorders: Diarrhea, nausea.
General Disorders and Administration Site Conditions: Asthenia, fatigue.
Musculoskeletal and Connective Tissue Disorders: Muscle spasm.
Nervous System Disorders: Dizziness, postural dizziness.
Respiratory, Thoracic and Mediastinal Disorders: Cough.
Chlorthalidone: The following adverse reactions have been observed in clinical trials of chlorthalidone: Rash, headache, dizziness, gastrointestinal upset and elevations of uric acid and cholesterol.
Clinical Laboratory Findings with Edarbyclor: In the factorial design trial, clinically relevant changes in standard laboratory parameters were uncommon with administration of the recommended doses of Edarbyclor.
Renal Parameters: Increased blood creatinine is a known pharmacologic effect of renin-angiotensin aldosterone system (RAAS) blockers such as ARBs and ACE inhibitors, and is related to the magnitude of blood pressure reduction. The incidence of consecutive increases of creatinine ≥50% from baseline and >ULN was 2% in patients treated with the recommended doses of Edarbyclor compared with 0.4% and 0.3% with azilsartan medoxomil and chlorthalidone, respectively. Elevations of creatinine were typically transient, or non-progressive and reversible, and associated with large blood pressure reductions.
Mean increases in blood urea nitrogen (BUN) were observed with Edarbyclor (5.3 mg/dL) compared with azilsartan medoxomil (1.5 mg/dL) and with chlorthalidone (2.5 mg/dL).
Post-Marketing Experience: The following adverse reactions have been identified during the post-marketing use of Edarbyclor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nausea, rash, pruritus, angioedema.
Drug Interactions
Edarbyclor: The pharmacokinetics of azilsartan medoxomil and chlorthalidone are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with other drugs and Edarbyclor, although studies have been conducted with azilsartan medoxomil and chlorthalidone.
Azilsartan Medoxomil: No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone and warfarin. Therefore, azilsartan medoxomil may be used concomitantly with these medications.
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 inhibitor 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 co-administer aliskiren with Edarbyclor in patients with diabetes. Avoid use of aliskiren with Edarbyclor in patients with renal impairment (GFR <60 mL/min).
Chlorthalidone: Lithium renal clearance is reduced by diuretics eg, chlorthalidone, increasing the risk of lithium toxicity. Consider monitoring lithium levels when using Edarbyclor.
Storage
Store below 30°C in the original blister.
ATC Classification
C09DA09 - azilsartan medoxomil and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab 40/12.5 mg (pale red, round, biconvex, 9.7 mm in diameter with "A/C" and "40/12.5" imprinted on one side) x 4 x 7's. 40/25 mg (light red, round, biconvex, 9.7 mm in diameter with "A/C" and "40/25" imprinted on one side) x 4 x 7's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in