EDARBYCLOR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for EDARBYCLOR (EDARBYCLOR).
EDARBYCLOR is a fixed-dose combination of azilsartan medoxomil, an angiotensin II receptor blocker (ARB), and chlorthalidone, a thiazide-like diuretic. Azilsartan selectively blocks AT1 receptors, reducing angiotensin II-mediated vasoconstriction, aldosterone secretion, and renal sodium reabsorption. Chlorthalidone inhibits sodium-chloride cotransport in the distal convoluted tubule, increasing excretion of sodium, chloride, and water, thereby reducing plasma volume.
| Metabolism | Azilsartan medoxomil is hydrolyzed to the active metabolite azilsartan; azilsartan is metabolized primarily by CYP2C9. Chlorthalidone is minimally metabolized, with most of the dose excreted unchanged in urine. |
| Excretion | Renal (approximately 60% as unchanged drug and metabolites), biliary/fecal (approximately 40%) |
| Half-life | Terminal elimination half-life is approximately 11-12 hours for azilsartan medoxomil; clinical consequence: supports once-daily dosing for 24-hour blood pressure control |
| Protein binding | Azilsartan: >99% bound to serum albumin; chlorthalidone: approximately 75% bound to albumin and lipoproteins |
| Volume of Distribution | Azilsartan: approximately 16 L (0.2 L/kg) indicating limited extravascular distribution; chlorthalidone: approximately 3-4 L/kg (extensive tissue binding, particularly to erythrocytes) |
| Bioavailability | Azilsartan medoxomil: absolute bioavailability approximately 60% (oral); chlorthalidone: approximately 65% (oral) |
| Onset of Action | Oral: initial antihypertensive effect observed within 2 hours, maximal effect by 4-6 hours |
| Duration of Action | Duration of action is approximately 24 hours, consistent with once-daily dosing; sustained trough-to-peak ratio >50% |
| Molecular Weight | Azilsartan medoxomil: 568.6 Da; Chlorthalidone: 338.8 Da. (Combination: two active components) |
One tablet (azilsartan medoxomil 40 mg / chlorthalidone 12.5 mg or 40 mg / 25 mg) orally once daily.
| Dosage form | TABLET |
| Renal impairment | eGFR <30 mL/min/1.73m2: not recommended. No adjustment required for eGFR ≥30 mL/min/1.73m2. |
| Liver impairment | Child-Pugh Class A (mild): no adjustment. Child-Pugh Class B (moderate): contraindicated. Child-Pugh Class C (severe): contraindicated. |
| Pediatric use | Not established; safety and efficacy in pediatric patients have not been studied. |
| Geriatric use | Initiate with the lowest available dose (40 mg/12.5 mg) and titrate cautiously due to increased risk of hypotension and electrolyte disturbances. |
| 1st trimester | Avoid. Drugs acting directly on the renin-angiotensin-aldosterone system (RAAS) can cause fetal renal dysfunction, oligohydramnios, and skull ossification defects when used during the first trimester. Potential fetal toxicity outweighs benefits. |
| 2nd trimester | Contraindicated. Fetal risk includes oligohydramnios, fetal renal impairment, anuria, pulmonary hypoplasia, and death. Second and third trimester use is associated with severe fetal and neonatal outcomes. |
| 3rd trimester | Contraindicated. Same risks as second trimester; also may cause neonatal hypotension, hyperkalemia, and irreversible renal injury. |
Clinical note
Comprehensive clinical and safety monograph for EDARBYCLOR (EDARBYCLOR).
| Placental transfer | Limited data on azilsartan; however, other ARBs cross the placenta and are detected in fetal circulation. Chlorthalidone crosses the placenta and is associated with fetal electrolyte disturbances and thrombocytopenia. Given the combination, placental transfer is expected. |
| Breastfeeding |
■ FDA Black Box Warning
None
| Serious Effects |
Pregnancy (second and third trimesters)Hypersensitivity to azilsartan, chlorthalidone, or any component of the formulationAnuriaConcomitant use with aliskiren in patients with diabetes mellitusSevere renal impairment (CrCl <30 mL/min)
| Precautions | Fetal toxicity: Drugs acting directly on the renin-angiotensin system can cause oligohydramnios, fetal renal dysfunction, and neonatal hypotension, hyperkalemia, and skull hypoplasia. Discontinue Edarbyclor as soon as possible when pregnancy is detected., Hypotension: Correct volume- or salt-depleted patients prior to initiation; monitor for symptomatic hypotension., Electrolyte disturbances: Chlorthalidone may cause hypokalemia, hyponatremia, and hypomagnesemia. Monitor electrolytes periodically., Renal function deterioration: Monitor renal function in patients with renal artery stenosis, severe heart failure, or volume depletion., Hyperkalemia: Risk increased with renal impairment, diabetes, or concomitant use of potassium-sparing diuretics, potassium supplements, or other drugs that increase potassium., Acute angle-closure glaucoma: Chlorthalidone, as a sulfonamide derivative, can cause idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma., Exacerbation of systemic lupus erythematosus: Chlorthalidone may exacerbate or activate SLE., Metabolic: Chlorthalidone may increase serum glucose, uric acid (precipitating gout), and decrease urinary calcium excretion., Sulfonamide allergy: Chlorthalidone is a sulfonamide derivative; caution in patients with sulfonamide allergy. |
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| Both azilsartan and chlorthalidone are excreted in human milk. Chlorthalidone may suppress lactation or cause neonatal electrolyte disturbances. Due to potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during therapy. |
| Lactation Rating | Avoid |
| Teratogenic Risk | First trimester: Drugs acting directly on the renin-angiotensin system (RAS) can cause fetal renal dysplasia, oligohydramnios, and skull ossification defects when used in the second and third trimesters. There is no known risk of major malformations with first trimester exposure, but data are limited. Second and third trimesters: Use is contraindicated due to fetal renal dysfunction, oligohydramnios, pulmonary hypoplasia, limb contractures, and neonatal anuria, hypotension, and death. Azilsartan medoxomil (ARB) and chlorthalidone (thiazide diuretic) both affect RAS and fetal hemodynamics. |
| Fetal Monitoring | Monitor maternal blood pressure, serum electrolytes (especially potassium), renal function, and urine output. For fetuses, monitor ultrasound for amniotic fluid volume (oligohydramnios) and fetal growth. If oligohydramnios occurs, consider discontinuation of EDARBYCLOR. |
| Fertility Effects | No human data. In animal studies, azilsartan medoxomil did not impair fertility in rats. Chlorthalidone may cause slight transient decrease in sperm count in some species. Clinical relevance unknown. |
| Food/Dietary | Avoid high-potassium foods (e.g., bananas, oranges, potatoes, tomatoes, salt substitutes) in excess due to risk of hyperkalemia. Avoid excessive salt intake. Grapefruit juice may alter drug metabolism; limit or avoid consumption. Alcohol may potentiate hypotensive effects. |
| Clinical Pearls | EDARBYCLOR is a fixed-dose combination of azilsartan medoxomil (an ARB) and chlorthalidone (a thiazide-like diuretic). Monitor renal function and electrolytes regularly due to risk of hypotension, hyperkalemia, and hyponatremia. Avoid use in patients with anuria or severe renal impairment (eGFR <30 mL/min). Chlorthalidone may exacerbate gout and hyperuricemia. Use caution in patients with hepatic impairment or diabetes. |
| Patient Advice | Take this medication exactly as prescribed, usually once daily. · Avoid salt substitutes containing potassium unless approved by your doctor. · Drink plenty of fluids unless otherwise directed by your healthcare provider. · Report symptoms of low blood pressure (dizziness, fainting), electrolyte imbalance (muscle cramps, weakness), or kidney problems (decreased urination). · This drug may cause dizziness; avoid driving or operating machinery until you know how it affects you. · Tell your doctor if you are pregnant or planning to become pregnant; this drug can cause fetal harm. · Limit alcohol intake as it may worsen side effects. · Do not stop taking this medication abruptly without consulting your doctor. |