Azilsartan (Edarbi)
azilsartan medoxomil
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hypertension | Adults (≥18 years) | Monotherapy or combination | FDA Approved |
Azilsartan medoxomil is the newest ARB, approved by the FDA in February 2011 for the treatment of hypertension in adults. It is a prodrug that is hydrolysed to azilsartan during gastrointestinal absorption. In pivotal head-to-head studies, azilsartan 80 mg demonstrated statistically superior blood pressure reduction compared with valsartan 320 mg and olmesartan 40 mg at their maximum approved doses, making it distinct among ARBs for having shown superiority over other agents in the same class. There are no controlled trials demonstrating cardiovascular risk reduction with azilsartan (FDA PI), and it does not carry a heart failure or CV event reduction indication.
Diabetic nephropathy / proteinuria reduction: As with all ARBs, azilsartan may be used off-label for renoprotection in diabetic kidney disease based on class-effect evidence. Evidence quality: Low (no azilsartan-specific RCTs for this endpoint).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — standard initiation | 80 mg once daily | 80 mg once daily | 80 mg/day | The recommended dose per FDA PI. Can be given with or without food. Most BP effect apparent within 1–2 weeks Dispense in original container; protect from light and moisture |
| Hypertension — patient on high-dose diuretics | 40 mg once daily | 40–80 mg once daily | 80 mg/day | FDA PI recommends considering 40 mg starting dose specifically for patients treated with high doses of diuretics. For other volume- or salt-depleted patients, correct depletion before initiation when possible (FDA PI Warnings 5.2) |
| Renal impairment (mild–severe, including ESRD) | 80 mg once daily | 80 mg once daily | 80 mg/day | No dose adjustment required. Azilsartan is not dialysable. Monitor renal function in patients ≥75 years or with moderate-severe impairment Creatinine elevations may be more common in elderly and those with existing renal disease (FDA PI) |
| Hepatic impairment (mild–moderate) | 80 mg once daily | 80 mg once daily | 80 mg/day | No dose adjustment required per FDA PI. Azilsartan has not been studied in severe hepatic impairment |
In pivotal 6-week head-to-head studies, azilsartan 80 mg produced significantly greater reductions in clinic systolic BP than valsartan 320 mg and olmesartan 40 mg. This is notable because these are the maximum approved doses of these comparators. Azilsartan is the only ARB to have demonstrated statistically superior BP-lowering compared with other ARBs at their highest approved doses in randomised controlled trials.
Safety and effectiveness of azilsartan medoxomil in paediatric patients have not been established (FDA PI).
Pharmacology
Mechanism of Action
Azilsartan medoxomil is an orally active prodrug that is rapidly hydrolysed by esterases in the gastrointestinal tract to release azilsartan, the active moiety. Azilsartan selectively blocks the binding of angiotensin II to the AT1 receptor, inhibiting angiotensin II–mediated vasoconstriction, aldosterone secretion, sympathetic activation, and sodium reabsorption. A single dose equivalent to 32 mg inhibited the maximal pressor effect of exogenous angiotensin II by approximately 90% at peak and approximately 60% at 24 hours. Notably, azilsartan has been described as having inverse agonist properties at the AT1 receptor, meaning it may suppress constitutive (ligand-independent) receptor signalling in addition to blocking angiotensin II–stimulated activity. This dual mechanism may contribute to the enhanced blood pressure lowering observed in head-to-head comparisons with other ARBs. Azilsartan does not inhibit ACE (kininase II), so bradykinin-mediated cough is not expected.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Prodrug hydrolysed in GI tract; bioavailability ~60%; Tmax 1.5–3 h; dose-proportional PK over 20–320 mg; food does not affect bioavailability | Can be taken with or without food. Linear PK simplifies dose–response predictions. Steady state achieved in 5 days with no accumulation |
| Distribution | Vd ~16 L; protein binding >99% (serum albumin) | Modest Vd indicates predominantly intravascular distribution. High protein binding means displacement interactions unlikely at therapeutic concentrations |
| Metabolism | CYP2C9 to two inactive metabolites: M-I (O-deethylation, ~50% of azilsartan exposure) and M-II (decarboxylation, <1%); prodrug is not detected in plasma | CYP2C9 involvement means caution with strong CYP2C9 modulators is theoretically warranted, though no clinically significant interactions were observed in studies with fluconazole or ketoconazole (FDA PI) |
| Elimination | t½ ~11 h; renal clearance ~2.3 mL/min; ~55% faeces, ~42% urine (15% as unchanged azilsartan); not dialysable | Once-daily dosing provides adequate 24-hour coverage based on AT1 receptor binding kinetics. Dual elimination pathway means no single organ failure dramatically alters exposure |
Side Effects
Azilsartan medoxomil has been evaluated for safety in 4,814 patients at doses of 20, 40, and 80 mg in clinical trials, including 1,704 treated for at least 6 months and 588 for at least 1 year. Treatment was well tolerated with an overall adverse event incidence similar to placebo. Adverse reactions were generally mild, not dose-related, and similar regardless of age, gender, and race (FDA PI).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhoea | 2% (vs 0.5% placebo) | Most common adverse reaction in the FDA PI; reported at 80 mg dose in placebo-controlled monotherapy trials; generally self-limiting |
Other adverse reactions reported at ≥0.3% and greater than placebo include nausea, asthenia, fatigue, muscle spasm, dizziness, postural dizziness, and cough (FDA PI). These were not common enough to appear at ≥1% above placebo in the AE table.
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Fetal toxicity | Class effect | 2nd/3rd trimester exposure | Discontinue immediately upon detection of pregnancy |
| Hypotension / orthostatic hypotension | 0.4% (leading to discontinuation; 0% placebo) | Initiation, especially in volume-depleted patients | Supine positioning; IV fluids; consider 40 mg starting dose in at-risk patients |
| Angioedema | Rare (post-marketing reports) | Any time during treatment | Discontinue permanently; emergency airway management |
| Sprue-like enteropathy | Very rare (post-marketing reports; ARB class concern) | Months to years after initiation | Discontinue azilsartan; investigate for coeliac disease; symptoms typically resolve after drug withdrawal |
| Acute renal failure | Rare | Days to weeks, especially in volume-depleted or renal artery stenosis | Hold drug; volume resuscitation; reassess RAS blockade |
| Hyperkalaemia | Uncommon (higher with concomitant K-sparing agents or renal impairment) | Weeks | Reduce or stop dose; correct potassium; review concomitant medications |
Lab findings: Low haemoglobin (0.2%), low haematocrit (0.4%), low RBC count (0.3%). A small, reversible increase in serum creatinine was observed with azilsartan 80 mg (FDA PI).
Azilsartan has a notably clean side-effect profile. Diarrhoea at 2% is the only adverse reaction listed at ≥1% and greater than placebo. The discontinuation rate was comparable to placebo (2.2–2.7% vs 2.4%), and no patients in clinical trials discontinued due to abnormal hepatic function. No rebound hypertension was observed upon abrupt cessation.
Drug Interactions
Azilsartan is metabolised by CYP2C9. Despite this, the FDA PI reports no clinically significant drug interactions in studies with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, or warfarin. The key interactions are pharmacodynamic, centring on dual RAS blockade and potassium homeostasis.
Monitoring
-
Blood Pressure
Each visit; 1–2 weeks after initiation
Routine Most antihypertensive effect apparent within 1–2 weeks. No rebound hypertension observed on abrupt cessation. Effect is smaller (~half) in Black patients as monotherapy (FDA PI). -
Serum Potassium
Baseline; periodically
Routine Particularly important with concomitant K-sparing agents or renal impairment. No clinically significant potassium changes were observed in hypertension monotherapy trials (FDA PI). -
Renal Function
Baseline; periodically
Routine A small, reversible creatinine increase was observed with 80 mg. Patients ≥75 years and those with moderate-severe renal impairment are more likely to experience elevated creatinine (FDA PI). Monitor more closely with concomitant NSAIDs. -
Haemoglobin / Haematocrit
As clinically indicated
Trigger-based Low Hb (0.2%), low Hct (0.4%), and low RBC count (0.3%) observed in trials. Check if anaemia symptoms develop. -
Pregnancy Status
Before initiation
Routine Discontinue immediately when pregnancy is detected (FDA boxed warning).
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity (e.g., anaphylaxis or angioedema) to azilsartan medoxomil or any component
- Pregnancy (2nd and 3rd trimesters — FDA boxed warning)
- Co-administration with aliskiren in patients with diabetes mellitus
Relative Contraindications (Specialist Input Recommended)
- Bilateral renal artery stenosis or stenosis of a solitary kidney — anticipated risk of acute renal failure (analogous to ACE inhibitors per FDA PI)
- Severe hepatic impairment — azilsartan has not been studied in this population
Use with Caution
- Volume or salt depletion — correct before initiating or consider starting at 40 mg
- Patients ≥75 years or with moderate-severe renal impairment — more likely to experience elevated creatinine (FDA PI)
- Patients of Black race — BP-lowering effect as monotherapy is approximately half that of other racial groups; consider combination therapy
- History of angioedema from ACE inhibitors — cross-reactivity possible though rare; use with caution
Drugs that act directly on the renin–angiotensin system can cause injury and death to the developing fetus. Reported complications include oligohydramnios, skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, azilsartan medoxomil should be discontinued as soon as possible.
Patient Counselling
Purpose of Therapy
Azilsartan helps lower blood pressure by blocking the effects of angiotensin II, a hormone that narrows blood vessels. Lowering blood pressure reduces the long-term risk of stroke and heart attack. This medication is taken once daily and works steadily throughout the day.
How to Take
Take azilsartan once daily at the same time each day, with or without food. Tablets should remain in the original container and be protected from moisture and light. Do not stop taking azilsartan without consulting your prescriber, even if you feel well.
Sources
- Arbor Pharmaceuticals / Takeda. Edarbi (azilsartan medoxomil) tablets — FDA-approved prescribing information. DailyMed Primary regulatory source for all indications, dosing, PK data, adverse event rates, and contraindications cited in this monograph.
- Edarbi (azilsartan medoxomil) tablets — FDA Label 2024. FDA Most recent FDA label version with updated safety and PK information.
- White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011;57(3):413–420. DOI Pivotal 6-week trial demonstrating azilsartan 80 mg superiority over valsartan 320 mg and olmesartan 40 mg in clinic SBP reduction.
- Bakris GL, Sica D, Weber M, et al. The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. J Clin Hypertens. 2011;13(2):81–88. DOI Head-to-head trial confirming azilsartan 80 mg superiority over olmesartan 40 mg in 24-hour ambulatory BP.
- Sica D, White WB, Weber MA, et al. Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring. J Clin Hypertens. 2011;13(7):467–472. DOI Supporting trial confirming sustained 24-hour BP reduction with azilsartan vs valsartan.
- Jones DW, Ferdinand KC, Taler SJ, et al. 2025 AHA/ACC guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. J Am Coll Cardiol. 2025;86(18):1567–1678. PubMed Most current US hypertension guideline; includes ARBs as first-line antihypertensive agents.
- Ojima M, Igata H, Tanaka M, et al. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies. J Pharmacol Exp Ther. 2011;336(3):801–808. DOI Demonstrates azilsartan’s potent and sustained AT1 receptor binding and potential inverse agonist properties distinguishing it from other ARBs.
- Jones JD, Jackson SH, Agboton C, Martin TS. Azilsartan medoxomil (Edarbi): the eighth angiotensin II receptor blocker. P T. 2011;36(10):634–640. PMC Comprehensive review of azilsartan’s pharmacology, clinical trials, safety profile, and positioning among ARBs at the time of FDA approval.
- Zhu L, Wei GC, Xiao Q, et al. Efficacy and safety of azilsartan medoxomil in the treatment of hypertension: a systematic review and meta-analysis. Front Cardiovasc Med. 2024;11:1383217. DOI Recent systematic review and meta-analysis confirming azilsartan’s efficacy and favourable safety profile across multiple randomised trials.
- Wang JG, Zhang M, Feng YQ, et al. Is the newest angiotensin-receptor blocker azilsartan medoxomil more efficacious in lowering blood pressure than the older ones? A systematic review and network meta-analysis. J Clin Hypertens. 2021;23(5):901–914. DOI Network meta-analysis confirming azilsartan’s superior BP-lowering efficacy compared with other ARBs.