Avoid use in pregnancy. When pregnancy is detected, discontinue azilsartan as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Hypertension, chronic:
Note: For patients who warrant combination therapy (BP >20/10 mm Hg above goal or suboptimal response to initial monotherapy), may use with another appropriate agent (eg, long-acting dihydropyridine calcium channel blocker or thiazide diuretic) (ACC/AHA [Whelton 2018]).
Oral: Initial: 40 mg once daily; evaluate response after ~2 to 4 weeks and titrate dose as needed up to 80 mg once daily; if additional BP control is needed, consider combination therapy (ACC/AHA [Whelton 2018]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary; however, carefully monitor the patient.
Mild to moderate impairment: No dosage adjustment necessary; however, carefully monitor the patient.
Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied). Should be used with caution in patients with ascites due to cirrhosis (AASLD [Biggins 2021]; AASLD [Runyon 2013]).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as medoxomil:
Edarbi: 40 mg, 80 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as medoxomil:
Edarbi: 40 mg, 80 mg
Oral: Administer without regard to food.
Hypertension, chronic: Management of hypertension.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%: Gastrointestinal: Diarrhea (≤2%)
Frequency not defined:
Cardiovascular: Hypotension, orthostatic hypotension
Central nervous system: Dizziness, fatigue, orthostatic dizziness
Gastrointestinal: Nausea
Neuromuscular & skeletal: Asthenia, muscle spasm
Renal: Increased serum creatinine
Respiratory: Cough
<1%, postmarketing, and/or case reports: Angioedema, decreased hematocrit, decreased hemoglobin, decreased red blood cells, leukocytosis, pruritus, skin rash, thrombocytopenia
Concomitant use with aliskiren-containing products in patients with diabetes mellitus.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to azilsartan medoxomil or any component of the formulation; concomitant use with aliskiren-containing drugs in patients with moderate to severe kidney impairment (GFR <60 mL/minute/1.73 m2); pregnancy; breastfeeding.
Documentation of allergenic cross-reactivity for angiotensin II receptor blockers is limited. However, because of similarities in chemical structure and/or pharmacological actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Angioedema: Angiotensin II receptor antagonists (ARBs) do not appear to elevate the risk of angioedema (Rasmussen 2019; Toh 2012). Patients with a history of angioedema due to an angiotensin-converting enzyme inhibitor must be educated that sometimes there can be recurrence within months following discontinuation (Beltrami 2011). No matter the cause of angioedema, prolonged frequent monitoring is required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Discontinue therapy immediately if angioedema occurs. Aggressive early management is critical. IM administration of epinephrine may be necessary. Do not readminister to patients who have had angioedema with ARBs.
• Hyperkalemia: May occur in patients taking ARBs; risk factors include kidney dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Hypotension: Symptomatic hypotension may occur upon initiation in patients who are salt- or volume-depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration. This transient hypotensive response is not a contraindication to further treatment with azilsartan.
• Kidney function deterioration: May be associated with deterioration of kidney function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure, volume depletion) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute kidney failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in kidney function.
Disease-related concerns:
• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.
• Ascites: Generally, avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor BP and kidney function carefully to avoid rapid development of kidney failure (AASLD [Runyon 2013]).
• Kidney impairment: Use with caution in preexisting kidney insufficiency.
• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in kidney function unless possible benefits outweigh risks.
Special populations:
• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
• Race/Ethnicity: In Black patients, the BP-lowering effects of ARBs may be less pronounced. The exact mechanism is not known; differences in the renin-angiotensin-aldosterone system, low renin levels, and salt sensitivity more commonly found in Black patients may contribute (Brewster 2013; Helmer 2018; manufacturer's labeling).
• Surgical patients: In patients on chronic ARB therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).
Substrate of CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Aliskiren: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Risk D: Consider therapy modification
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin II: Receptor Blockers may diminish the therapeutic effect of Angiotensin II. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of Angiotensin-Converting Enzyme Inhibitors. Management: Use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives when possible. Monitor blood pressure, renal function, and potassium if combined. Risk D: Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Finerenone: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Heparin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Initiate lithium at lower doses in patients receiving an angiotensin II receptor blocker (ARB). Consider lithium dose reductions in patients stable on lithium therapy who are initiating an ARB. Monitor lithium concentrations closely when combined. Risk D: Consider therapy modification
Loop Diuretics: May enhance the hypotensive effect of Angiotensin II Receptor Blockers. Loop Diuretics may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May diminish the therapeutic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Ranolazine: May enhance the adverse/toxic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Tacrolimus (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
The use of angiotensin II receptor blockers should generally be avoided in patients planning a pregnancy (ACOG 2019).
[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue as soon as possible. The use of drugs which act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal kidney function, may lead to fetal lung hypoplasia and skeletal malformations. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Use in pregnancy is also associated with anuria, hypotension, kidney failure, skull hypoplasia, and death in the fetus/neonate. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed in utero should be monitored for hyperkalemia, hypotension, and oliguria (exchange transfusions or dialysis may be needed). These adverse events are generally associated with maternal use in the second and third trimesters.
Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant. The risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death may be increased with chronic hypertension in pregnancy. Actual risks may be related to duration and severity of maternal hypertension (ACOG 2019).
The use of angiotensin II receptor blockers is generally not recommended to treat chronic hypertension in pregnant patients (ACOG 2019).
It is not known if azilsartan is present in breast milk.
Due to the potential for adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Baseline and periodic BP; electrolytes, serum creatinine, BUN.
BP goals: May vary depending on clinical condition, different clinical practice guidelines, and expert opinion. Refer to clinical practice guidelines for specific treatment goals.
Angiotensin II (which is formed by enzymatic conversion from angiotensin I) is the primary pressor agent of the renin-angiotensin system. Effects of angiotensin II include vasoconstriction, stimulation of aldosterone synthesis/release, cardiac stimulation, and renal sodium reabsorption. Azilsartan inhibits angiotensin II’s vasoconstrictor and aldosterone-secreting effects by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle and adrenal gland tissues (azilsartan has a stronger affinity for the AT1 receptor than the AT2 receptor). The action is independent of the angiotensin II synthesis pathways. Azilsartan does not inhibit ACE (kininase II), therefore it does not affect the response to bradykinin (the clinical relevance of this is unknown) and does not bind to or inhibit other receptors or ion channels of importance in cardiovascular regulation.
Distribution: Vd: ~16 L
Protein binding: >99%; primarily to serum albumin
Metabolism: Gut: prodrug hydrolyzed to active metabolite; Hepatic: primarily via CYP2C9 to inactive metabolites
Bioavailability: ~60%
Half-life elimination: ~11 hours
Time to peak, serum: 1.5-3 hours
Excretion: Feces (~55%); urine (~42%, 15% as unchanged drug)
Clearance: 2.3 mL/minute
Tablets (Edarbi Oral)
40 mg (per each): $8.34
80 mg (per each): $9.06
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