EDARBI

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.

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.

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.

Used to treat hypertension.

Carefully used under the supervision of a doctor in the following cases: kidney or liver diseases; unbalanced levels of potassium and magnesium in blood; dehydration or heart disease; and period of breastfeeding.

Mechanism of Action The active ingredients of Edarbyclor target two separate mechanisms involved in blood pressure regulation.

Azilsartan medoxomil Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II).

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 medoxomil is an orally administered prodrug that is rapidly converted by esterases during absorption to the active moiety, azilsartan.

Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 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 AT 2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis.

Azilsartan has more than a 10,000-fold greater affinity for the AT 1 receptor than for the AT 2 receptor.

Blockade of the renin-angiotensin 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 produces diuresis with increased excretion of sodium and chloride.

The site of action appears to be the distal renal tubule (early convoluted part), inhibiting NaCl reabsorption (by antagonizing the Na+-Cl-cotransporter) and promoting Ca++ reabsorption (by an unknown mechanism).

The enhanced delivery of

Na+ and water to the cortical collecting tubule and/or the increased flow rate leads to increased secretion and elimination of K+ and H+.

The diuretic effects of chlorthalildone 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. 12.2 Pharmacodynamics 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 32 mg azilsartan medoxomil 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.

The diuretic effect of chlorthalidone occurs in approximately 2.6 hours and continues for up to 72 hours. 12.3 Pharmacokinetics Edarbyclor Following oral administration of Edarbyclor, peak plasma concentrations of azilsartan and chlorthalidone are reached at and 1 hours, respectively.

The rate (C max and T max ) 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 C max of chlorthalidone from Edarbyclor was 45-47% higher.

There is no clinically significant effect of food on the bioavailability of azilsartan or chlorthalidone following administration of Edarbyclor.

Azilsartan medoxomil 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 concentrations (C max ) 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 16L.

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.

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.

Chlorthalidone crosses the placental barrier and passes into breast milk.

When mothers were treated before and after birth with 50 mg chlorthalidone daily, chlorthalidone levels in fetal whole blood were around 15% of those found in maternal blood.

Chlorthalidone concentrations in amniotic fluid and breast milk are approximately 4% of those found in maternal blood.

Metabolism and Elimination Azilsartan medoxomil

Azilsartan medoxomil, when administered alone or in combination with chlorthalidone is eliminated from plasma with an elimination half-life of 11-13 hours.

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 14 C-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 when administered alone or in combination with azilsartan medoxomil is eliminated from plasma with an elimination half-life of 42-45 hours.

The elimination half-life is unaltered following repeat dosing.

The majority of an absorbed quantity of chlorthalidone is excreted by the kidneys with a mean renal clearance of 46-70 mL/min. By contrast, metabolism and excretion via the liver and bile play a minor role in the elimination of the substance.

Approximately 60%-70% of chlorthalidone is excreted in the urine and feces within 120 hours, mainly in unchanged form.

Specific 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 as change relative to reference (test/reference).

Figure 2.

Impact of intrinsic factors on the pharmacokinetics of azilsartan Figure 2 Drug Interactions 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.

An antigenotensin 2 (Angiotensin Receptor Blockers), where blood pressure is prevented, and thus reduced and improved blood flow.

The following potential adverse reactions with

Edarbyclor, azilsartan medoxomil, or chlorthalidone and similar agents are included in more detail in the Warnings and Precautions section of the label: Fetal toxicity Hypotension in Volume.

• or Salt-Depleted Patients Impaired Renal Function Hypokalemia Hyperuricemia Most common adverse reactions (incidence ≥2%) are dizziness and fatigue To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc.fda.gov/medwatch. 6.1 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 3900 patients with hypertension; more than 700 patients were treated for at least 6 months and more than 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 1.

Table 1.

Adverse Reactions Occurring at an

Incidence of ≥2% of Edarbyclor-treated Patients and > Azilsartan medoxomil or Chlorthalidone Preferred Term Azilsartan medoxomil 20, 40, 80 mg (N=470) Chlorthalidone 12.5, 25 mg (N=316) Edarbyclor 40 / 12.5, 40 / 25 mg (N=302) Dizziness 1.7% 1.9% 8.9% Fatigue 0.6% 1.3% 2.0% 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 serum creatinine increased (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 4814 patients were evaluated for safety when treated with azilsartan medoxomil at doses of 20, 40 or 80 mg in clinical trials.

This includes 1704 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 3300 patients treated with azilsartan medoxomil in controlled trials are listed below: Gastrointestinal.

Disorders: diarrhea, nausea General.

Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue.

Disorders: muscle spasm Nervous System.

Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal.

Disorders: cough Chlorthalidone The following adverse reactions have been observed in clinical trials of chlorthalidone: rash, headache, dizziness, GI upset, and elevations of uric acid and cholesterol.

In the factorial design trial, clinically relevant changes in standard laboratory parameters were uncommon with administration of the recommended doses of Edarbyclor.

Renal parameters

The incidence of consecutive increases of creatinine ≥50% from baseline and >ULN was 2.0% in patients treated with the recommended doses of Edarbyclor compared with 0.4% and 0.3% with azilsartan medoxomil and chlorthalidone, respectively.

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). 6.2 Postmarketing Experience The following adverse reactions have been identified during the postmarketing 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.

Loss of consciousness Pruritus

Limited data are available related to overdosage in humans.

Azilsartan medoxomil

During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of azilsartan medoxomil 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.

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.

Edarbyclor is contraindicated in patients with anuria.

Do not coadminister aliskiren-containing products with

Edarbyclor in patients with diabetes.

Anuria Do not coadminister aliskiren-containing products with Edarbyclor in patients with diabetes.

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 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 to 2 weeks.

The dosage may be increased to 40/25 mg after 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. 2.2 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. 2.3 Handling Instructions Do not repackage Edarbyclor.

Dispense and store Edarbyclor in its original container to protect Edarbyclor from light and moisture.

Edarbyclor is supplied as fixed dose combination tablets that are round, biconvex, film-coated, and 9.7 mm in diameter.

Bottle of 30 40 / 12.5 mg Pale red A/C 40/12.5 60631-412-30 40 / 25 mg Light red A/C 40/25 75929-230-03 Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F) .

Keep container tightly closed.

Protect from moisture and light.

Do not repackage; dispense and store in original container.

Store at 25°C (77°F), excursions permitted to 15°-30°C (59°-86°F) .

Keep container tightly closed.

Protect from moisture and light.

Do not repackage; dispense and store in original container.

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.

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.

When pregnancy is detected, discontinue Edarbyclor as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal adverse reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

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.

In neonates with a history of in utero exposure to Edarbyclor, if oliguria or hypotension occurs, support blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults.

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 coadministration of azilsartan medoxomil, M-II, and chlorthalidone.

With the exception of these findings, there were no toxicologically synergistic effects in this study.

In an embryo-fetal 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/m 2 basis.

Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m 2 basis) or up to 50 mg azilsartan medoxomil/kg/day to pregnant rabbits (12 times the MRHD on a mg/m 2 basis).

M-II also was not teratogenic in rats or rabbits at doses up to 3000 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.

Safety and effectiveness of

Edarbyclor in pediatric patients under 18 years of age have not been established.

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 of age or older); 5.7% were 75 years and older.

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.