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Azilsartan Medoxomil

C09C - Angiotensin II antagonists, plain ATC C09CA09 Small molecule approved 2011 Oral Prodrug Natural product Black-box warning

Active form: Azilsartan.

JFDA label: Edarbi 80mg Tablets

⚠ Black-Box Warning

Mechanism of Action

Sulfonamide-derived diuretic that inhibits sodium and chloride reabsorption in the cortical-diluting segment of the ascending loop of Henle

Indications

Approved

  • Chronic kidney disease (CKD) and hypertension
  • Coronary artery disease (CAD) and hypertension
  • Edema
  • Hypertension

Off-label

  • Calcium nephrolithiasis

Contraindications

Source: Lexicomp

  • Hypersensitivity to chlorthalidone, other sulfonamide-derived drugs, or any component of the formulation Absolute
  • anuria Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See "Warnings/Precautions" for more detail. Documentation of allergenic cross-reactivity for drugs thiazide-type diuretics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certai Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Metabolism and nutrition disorders (1)

Not Known Hypokalemia

Gastrointestinal disorders (2)

Not Known Anorexia · dyspepsia

Skin and subcutaneous tissue disorders (1)

Not Known Skin photosensitivity

Dosing

Source: Lexicomp

Edema: Oral: Initial: 50 to 100 mg once daily or 100 mg on alternate days; maximum: 200 mg/day Heart failure-associated edema: Oral: Initial: 12.5 to 25 mg once daily; maximum: 100 mg/day (ACCF/AHA [Yancy 2013]) Hypertension: Oral: Initial: 25 mg once daily or 12.5 mg once daily (JNC 8 [James 2013]); may increase after a suitable trial to 50 mg once daily; maximum: 100 mg/day; usual dosage range (ASH/ISH [Weber 2014]): 12.5 to 25 mg daily. Target dose range (JNC 8 [James 2013]): 12.5 to 25 mg daily. Calcium nephrolithiasis (off-label use): Oral: 25 mg once daily (AUA Guidelines [Pearle 2014])
(For additional information see "Chlorthalidone: Pediatric drug information") Hypertension (off-label use): Children and Adolescents: Oral: Initial: 0.3 mg/kg once daily, up to 2 mg/kg/day; maximum: 50 mg/day (NHBPEP 2004; NHLBI 2011)
Edema: Refer to adult dosing. Hypertension: Oral: Initial: 6.25 to 12.5 mg once daily or every other day; maximum: 25 mg/day (Carter 2004; SHEP 1991).
There are no dosage adjustments provided in the manufacturer's labeling (use is contraindicated with anuria). The following adjustments have been recommended (Aronoff 2007): CrCl ≥10 mL/minute: No dosage adjustment necessary. CrCl
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Warnings & Precautions

Source: Lexicomp

Electrolyte disturbances

Hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia may occur. Development of electrolyte disturbances can be minimized when used in combination with other electrolyte sparing antihypertensives (eg, ACE inhibitors or angiotensin receptor blockers) (Sica 2011).

Gout

In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated. This risk may be increased with doses ≥25 mg (in hydrochlorothiazide equivalents) (Gurwitz 1997).

Hypersensitivity reactions

Hypersensitivity reactions may occur. Risk is increased in patients with a history of allergy or bronchial asthma.

Photosensitivity

Photosensitization may occur.

Sulfonamide ("sulfa") allergy

The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes. Disease-related concerns:

Adrenal insufficiency

Avoid use of diuretics for treatment of elevated blood pressure in patients with primary adrenal insufficiency (Addison disease). Adjustment of glucocorticoid/mineralocorticoid therapy and/or use of other antihypertensive agents is preferred to treat hypertension (Bornstein 2016; Inder 2015).

Diabetes

Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.

Hepatic impairment

Use with caution in patients with severe hepatic impairment; in progressive or severe hepatic disease, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.

Hypercalcemia

Thiazide diuretics may decrease renal calcium excretion; consider avoiding use in patients with hypercalcemia.

Hypercholesterolemia

Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazide diuretics.

Hypokalemia

Use with caution in patients with hypokalemia; correct before initiating therapy.

Parathyroid disease

Thiazide diuretics reduce calcium excretion; pathologic changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been observed with prolonged use; should be discontinued prior to testing for parathyroid function.

Renal impairment

Cumulative effects may develop, including azotemia, in patients with impaired renal function. Avoid in severe renal disease (ineffective).

Systemic lupus erythematosus (SLE)

May cause SLE exacerbation or activation. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Surgical patients

If given the morning of surgery, thiazide diuretics may render the patient volume depleted and blood pressure may be labile during general anesthesia.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events have not been observed in animal reproduction studies. Chlorthalidone crosses the placenta and can be detected in cord blood. Maternal use may cause fetal or neonatal jaundice, thrombocytopenia, or other adverse events observed in adults. Use of thiazide diuretics to treat edema during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor. Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. Women who require thiazide diuretics for the treatment of hypertension prior to pregnancy may continue their use (ACOG 2013).

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in the breast-feeding infant, the manufacturer recommends a decision be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of treatment to the mother. Diuretics have the potential to decrease milk volume and suppress lactation.

Monitoring

Clinical pearlMonitor weight, I & O records daily to determine fluid loss; blood pressure, serum electrolytes, renal function

Chemistry & Properties

2D structure
FormulaC30H24N4O8
Molecular weight568.54 g/mol
IUPAC name(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-3-[[4-[2-(5-oxo-4H-1,2,4-oxadiazol-3-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate
CAS863031-21-4
PubChem CID135409642
InChIKeyQJFSABGVXDWMIW-UHFFFAOYSA-N
logP4.71 (XLogP 4.9)
Polar surface area155.59 Ų
H-bond acceptors / donors11 / 1
Drug-likeness (QED)0.24
Lipinski violations2
SMILESCCOc1nc2cccc(C(=O)OCc3oc(=O)oc3C)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability70.0%
Half-life0.579 h
Volume of distribution0.21 L/kg
Protein binding98.9%
BBB penetrantNo

Enzyme interactions

EnzymeRoleDetail
CYP1A2Inhibitor
CYP1A2Substrate
CYP2B6Substrate
CYP2C8Inhibitor
CYP2C9Inhibitor
CYP2C9Substrate

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (85, DDInter)

Interacting drugSeverityManagement
Potassium Iodide major
Potassium acetate major
Potassium bicarbonate major
Potassium chloride major
Potassium citrate major
Potassium gluconate major
Acetylsalicylic acid moderate
Aldesleukin moderate
Alimemazine moderate
Amifostine moderate
Betamethasone moderate
Brimonidine (ophthalmic) moderate
Brimonidine (topical) moderate
Budesonide moderate
Bupropion moderate
Canagliflozin moderate
Celecoxib moderate
Chlorphenesin moderate
Codeine moderate
Corticotropin moderate
Cyclosporine moderate
Dalteparin moderate
Dapagliflozin moderate
Deflazacort moderate
Dexamethasone moderate
Diclofenac moderate
Diphenhydramine moderate
Doxepin moderate
Doxepin (topical) moderate
Dronabinol moderate
Empagliflozin moderate
Enoxaparin moderate
Epoprostenol moderate
Ertugliflozin moderate
Ethanol moderate
Everolimus moderate
Exenatide moderate
Fludrocortisone moderate
Flurbiprofen moderate
Heparin moderate

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Registered Products (4)

BrandForm / strengthPackAgentCitizen (JOD)
Edarbi Tablet 80 mg 28 tab The Arab Pharmaceutical Manufacturing PSC/Salt 14.850
Edarbi Tablet 40 mg 28 tab The Arab Pharmaceutical Manufacturing PSC/Salt 14.850
Edarbyclor 40mg/12.5 mg Tablet 12.5 mg, 40 mg 28 tab The Arab Pharmaceutical Manufacturing PSC/Salt 16.600
Edarbyclor 40mg/25 Tablet 25 mg, 40 mg 28 tab The Arab Pharmaceutical Manufacturing PSC/Salt 16.600