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Hypertension: Oral: Initial therapy: Azilsartan 40 mg/chlorthalidone 12.5 mg once daily; dose may be increased after 2-4 weeks of therapy to azilsartan 40 mg/chlorthalidone 25 mg once daily. Maximum recommended dose: Azilsartan 40 mg/day; chlorthalidone 25 mg/day Dosing: Geriatric Refer to adult dosing. Dosing: Renal Impairment Mild-to-moderate renal impairment (eGFR 30-90 mL/minute/1.73 m 2 ): No dosage adjustment necessary. Severe renal impairment (eGFR <30 mL/minute/1.73 m 2 ): Safety and effectiveness not established. Dosing: Hepatic Impairment Mild-to-moderate hepatic impairment: No initial dosage adjustment necessary; monitor patient carefully. Severe hepatic impairment: Safety and effectiveness not established; use with caution in patients with severe hepatic impairment. Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Tablet, oral: edarbyclor™: 40/12.5: Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg edarbyclor™: 40/25: Azilsartan medoxomil 40 mg and chlorthalidone 25 mg Generic Equivalent Available: U.S. No Administration May be administered without regard to meals. Use Treatment of hypertension Adverse Reactions Significant Reactions/percentages reported with combination product; also see individual agents. 1% to 10%: Cardiovascular: Hypotension (2%) Central nervous system: Dizziness (9%), fatigue (2%) Renal: Serum creatinine increased (2%), BUN increased <1% (Limited to important or life-threatening): Syncope Contraindications Concomitant use with aliskiren in patients with diabetes mellitus; anuria Warnings/Precautions

Concerns related to adverse effects: • Electrolyte disturbances: Hyperkalemia may occur in patients taking angiotensin II receptor blockers; risk factors include renal 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. Hypokalemia, hypochloremic alkalosis, and hyponatremia can occur with chlorthalidone. Incidence of chlorthalidone-associated hypokalemia is reduced when given as a combination with azilsartan. • 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/chlorthalidone. • Photosensitivity: Photosensitization may occur with chlorthalidone. • Renal function deterioration: May be associated with deterioration of renal 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 renal 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 renal function. • Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use of chlorthalidone in patients with thiazide or sulfonamide allergy is specifically contraindicated in product labeling; however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.

Disease-related concerns: • Aortic/mitral stenosis: Use azilsartan with caution in patients with significant aortic/mitral stenosis. • Diabetes: Use chlorthalidone with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. • Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated with chlorthalidone. • Hepatic impairment: Use chlorthalidone with caution in patients with severe hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. • Hypercalcemia: Thiazide diuretics (eg, chlorthalidone) may decrease renal calcium excretion; consider avoiding use in patients with hypercalcemia. • Hypercholesterolemia: Use chlorthalidone with caution in patients with moderate or high cholesterol concentrations. • Hypokalemia: Use chlorthalidone with caution in patients with hypokalemia; correct before initiating therapy. • Renal impairment: Use azilsartan with caution in pre-existing renal insufficiency and severe renal impairment. Avoid chlorthalidone in severe renal disease (ineffective); contraindicated in patients with anuria. • Systemic lupus erythematosus (SLE): Chlorthalidone can cause SLE exacerbation or activation.

Concurrent drug therapy issues: • Angiotensin-converting enzyme (ACE) inhibitors and renin inhibitors: Concomitant use of an ACE-inhibitor or renin inhibitor (eg, aliskiren) is associated with an increased risk of hypotension, hyperkalemia, and renal dysfunction. Concomitant use with aliskiren should be avoided in patients with GFR <60 mL/minute and is contraindicated in patients with diabetes mellitus (regardless of GFR).

Special populations: • Pregnancy: [U.S. 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. Metabolism/Transport Effects Refer to individual components. Drug Interactions (For additional information: Launch Lexi-Interact™ Drug Interactions Program ) ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy Alfuzosin: May enhance the hypotensive effect of Antihypertensives. 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: Avoid aliskiren use with ACEIs or ARBs in patients with diabetes or estimated glomerular filtration rate below 60 mL/min. In other patients receiving these combinations, monitor serum potassium, serum creatinine, and blood pressure periodically. Risk D: Consider therapy modification Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Risk C: Monitor therapy Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification Analgesics (Opioid): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy

Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification Analgesics (Opioid): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy Barbiturates: May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy Beta2-Agonists: May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy Canagliflozin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Canagliflozin may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy CarBAMazepine: Thiazide Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy CycloSPORINE (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Risk C: Monitor therapy Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy

Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy Licorice: May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy Multivitamins/Minerals (with ADEK, Folate, Iron): Thiazide Diuretics may enhance the hypercalcemic effect of Multivitamins/Minerals (with ADEK, Folate, Iron). Risk C: Monitor therapy Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. 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 OXcarbazepine: Thiazide Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. 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 OXcarbazepine: Thiazide Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. 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 Antihypertensives. Risk C: Monitor therapy Rifamycin Derivatives: May increase the metabolism of Angiotensin II Receptor Blockers. Risk C: Monitor therapy RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification

Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy Topiramate: Thiazide Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Risk D: Consider therapy modification Toremifene: Thiazide Diuretics may enhance the hypercalcemic effect of Toremifene. Risk C: Monitor therapy Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy Vitamin D Analogs: Thiazide Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy Pregnancy Risk Factor D ( show table ) Pregnancy Implications [U.S. 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. Also see individual agents. Lactation Excretion in breast milk unknown/not recommended

Pregnancy Risk Factor D ( show table ) Pregnancy Implications [U.S. 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. Also see individual agents. Lactation Excretion in breast milk unknown/not recommended Breast-Feeding Considerations Chlorthalidone can be detected in breast milk. It is not known if azilsartan is excreted into breast milk. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother. Dietary Considerations May be taken without regard to meals. Pricing: U.S. (Medi-Span®)

Tablets (Edarbyclor Oral) 40-12.5 mg (30): $109.60 40-25 mg (30): $109.60 Mechanism of Action Azilsartan: 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. Chlorthalidone: A sulfonamide-derived diuretic that inhibits sodium and chloride reabsorption in the cortical-diluting segment of the ascending loop of Henle. Pharmacodynamics/Kinetics See individual agents. Use of UpToDate is subject to the Subscription and License Agreement . Topic 17102 Version 11.0 © 2013 UpToDate, Inc. All rights reserved. | Subscription and License Agreement | Release: 21.6- C21.56 Licensed to: AsanBook Dig. Med. Lib. | Support Tag: [0504-118.195.65.247-458F631DC3-S244013.14]