Dosing and uses of Edarbyclor (azilsartan/chlorthalidone)
Adult dosage forms and strengths
azilsartan/chlorthalidone
tablet
- 40mg/12.5mg
- 40mg/25mg
Hypertension
Angiotensin II receptor blocker (ARB) and thiazide-like diuretic combination indicated for treatment of hypertension in patients not adequately controlled with monotherapy, or as initial therapy in patients likely to need multiple drugs to help achieve blood pressure goals
40 mg/12.5 mg PO qDay initially; may increase to 40 mg/25 mg after 2-4 weeks as needed to achieve blood pressure goals; not to exceed 40 mg/25 mg daily
Switching from ARB or diuretic monotherapy: Initiate with 40 mg/12.5 mg PO qDay
Renal & Hepatic Impairment
Renal impairment
- Mild-to-moderate (eGFR 30 mL/min/1.73 sq.meter or greater): No dose adjustment required
- Severe (eGFR <30 mL/min/1.73 sq.meter): Safety and effectiveness not established
- Chlorthalidone may precipitate azotemia
Hepatic impairment
- Mild-to-moderate: No dose adjustment required for azilsartan
- Severe: Azilsartan has not been studied in patients with severe hepatic impairment
- Chlorthalidone may cause mild alterations of fluid and electrolyte balance that may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease
Administration
Patients titrated to the individual components (ie, azilsartan and chlorthalidone) may instead receive the corresponding dose of Edarbyclor
Patients who experience dose-limiting adverse reactions on chlorthalidone monotherapy may be switched to Edarbyclor, initially with a lower dose of chlorthalidone
May be taken with or without food
Correct volume depletion prior to administration, particularly with impaired renal function or with high doses of diuretics
May be administered with other antihypertensive agents
Pediatric dosage forms and strengths
Safety and efficacy not established
Edarbyclor (azilsartan/chlorthalidone) adverse (side) effects
1-10%
Dizziness (8.9%)
Fatigue (2%)
Hypotension (1.7%)
<1%
Syncope (0.3%)
Postmarketing Reports
Nausea
Rash, pruritus, angioedema
Warnings
Black box warnings
When pregnancy is detected, discontinue as soon as possible; drugs affecting renin-angiotensin system causing oligohydramnios, which may result in fetal injury and/or death (also see Cautions)
Contraindications
Anuria
Do not coadminister aliskiren with ARBs or ACEIs in patients with diabetes
Cautions
Hyperuricemia
- Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics
Fetal toxicity
- Also see Black box warnings
- 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
- 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 symptomatic hypotension may occur after initiation of treatment; such patients are probably not good candidates to start therapy with more than one drug
- Correct volume prior to administration; if hypotension does occur, place patient in supine position and, if necessary, give an IV infusion of normal saline
- 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
- Monitor for worsening renal function in patients with renal impairment; consider withholding or discontinuing if progressive renal impairment becomes evident
- Azilsartan: Dual blockade of the renin angiotensin system with ARBs, ACE inhibitors, or aliskiren is associated with increased risk for hypotension, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy
- 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
- May cause renal failure in patients with renal artery stenosis
Electrolytes
- Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone; Edarbyclor attenuates chlorthalidone-associated hypokalemia
- Coadministration of digitalis may exacerbate adverse effects of hypokalemia
- Thiazide diuretics can cause hyponatremia and hypokalemia; drugs that inhibit the renin angiotensin system can cause hyperkalemia; monitor serum electrolytes periodically
Pregnancy and lactation
Pregnancy category: d
Discontinue as soon as possible when pregnancy is detected; use during second and third trimesters affects renin-angiotensin system causing oligohydramnios, which may result in fetal injury and/or death (see Black box warnings and Cautions)
Lactation: Unknown whether azilsartan distributed in breast milk, thiazide-like diuretics are excreted in human milk; consider alternate antihypertensive therapy or do not breastfeed
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Edarbyclor (azilsartan/chlorthalidone)
Mechanism of action
Angiotensin II blocker; displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water absorption, and hypertrophic responses
Chlorthalidone produces diuresis with increased excretion of sodium and chloride at the cortical diluting segment of the ascending limb of Henle’s loop of the nephron
Pharmacokinetics
Bioavailability: 60% (azilsartan)
Onset: 2.6 hr (chlorthalidone)
Duration: Up to 72 hr (chlorthalidone)
Peak Plasma Time: 3 hr (azilsartan); 1 hr (chlorthalidone)
Protein Bound: >99%, mainly to albumin (azilsartan); 75% bound to plasma protein and 58% of drug bound to albumin (chlorthalidone)
Chlorthalidone binding (whole blood): Predominantly bound to erythrocyte carbonic anhydrase
Vd: 16 L (azilsartan)
Half-life, elimination: 11-12 hr (azilsartan); 45 hr (chlorthalidone)
Renal clearance: 2.3 mL/min (azilsartan)
Excretion (azilsartan medoxomil): Feces 55%, urine 42%; active metabolite (azilsartan) 15% excreted in urine
Excretion (chlorthalidone): Major portion of drug excreted unchanged by the kidneys; nonrenal routes not clarified
Metabolism
- Azilsartan medoxomil is rapidly hydrolyzed to azilsartan, the active metabolite, in the GI tract during absorption
- Azilsartan metabolites: 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; these do no contribute to the pharmacologic activity
- Metabolized by: CYP2C9 (azilsartan)
