Azilsartan Medoxomil + Chlorthalidone

• Hypertension:
  Indicated for the treatment of essential hypertension. This fixed-dose combination is used when monotherapy with either agent is insufficient to control blood pressure. It helps reduce the risk of cardiovascular events associated with hypertension.
• Off-label/Clinically Accepted Uses:
  Occasionally used in patients with resistant hypertension requiring combined renin-angiotensin system blockade and diuretic therapy. May also benefit certain patients with edema due to sodium retention.

Route: Oral

Adults:

• Initial dose typically contains 40 mg azilsartan medoxomil + 12.5 mg chlorthalidone once daily.
• Depending on response and tolerability, dose may be increased to 40 mg/25 mg once daily.
• Maximum dose: Usually 80 mg azilsartan medoxomil with 25 mg chlorthalidone (dose adjustments should be individualized).

Special Populations:

• Elderly: No specific dosage adjustment; monitor renal function and electrolytes carefully.
• Renal Impairment: Use cautiously in moderate impairment; contraindicated in severe impairment (eGFR <30 mL/min/1.73 m²) due to chlorthalidone component.
• Hepatic Impairment: Use with caution; no specific dosage adjustments but monitor liver function.

Administration Instructions:

• Taken once daily, with or without food.
• Administer at the same time each day for consistent effect.
• Tablets should be swallowed whole.

This combination works through complementary mechanisms:

• Azilsartan Medoxomil: A prodrug converted to azilsartan, selectively blocks angiotensin II type 1 (AT1) receptors, preventing angiotensin II–mediated vasoconstriction and aldosterone secretion, leading to vasodilation and decreased blood volume.
• Chlorthalidone: A thiazide-like diuretic that inhibits sodium and chloride reabsorption in the distal convoluted tubule of the nephron, increasing urine output and reducing plasma volume, which decreases cardiac output and systemic vascular resistance.

Together, they provide additive antihypertensive effects by reducing vascular resistance and plasma volume, improving blood pressure control.

• Absorption:
  Azilsartan medoxomil is well absorbed and rapidly hydrolyzed to active azilsartan; bioavailability ~60%.
  Chlorthalidone is well absorbed orally with peak plasma levels at 2–6 hours.
• Distribution:
  Azilsartan highly plasma protein bound (~99%).
  Chlorthalidone distributes widely, with a half-life of approximately 40–60 hours.
• Metabolism:
  Azilsartan undergoes hepatic metabolism primarily via CYP2C9.
  Chlorthalidone undergoes minimal metabolism.
• Elimination:
  Azilsartan is eliminated via feces and urine primarily as metabolites.
  Chlorthalidone is excreted mainly unchanged by the kidneys.
• Half-life:
  Azilsartan: ~11 hours
  Chlorthalidone: 40–60 hours (supporting once-daily dosing)

• Pregnancy:
  Classified as Category D by FDA due to azilsartan’s teratogenic effects and chlorthalidone’s potential risks during pregnancy. Contraindicated especially in second and third trimesters.
• Lactation:
  Unknown if either drug is excreted in human milk; breastfeeding is generally not recommended during treatment.

• Primary Therapeutic Class: Antihypertensive Combination
• Subclasses:
• Azilsartan: Angiotensin II receptor blocker (ARB)
• Chlorthalidone: Thiazide-like diuretic

• Known hypersensitivity to azilsartan, chlorthalidone, or any excipients.
• Anuria or severe renal impairment (eGFR <30 mL/min/1.73 m²).
• Pregnancy, especially second and third trimesters.
• Hypersensitivity to sulfonamide-derived drugs (chlorthalidone is sulfonamide derivative).
• Concomitant use with aliskiren in patients with diabetes or renal impairment.

• Monitor for hypotension, especially in volume- or salt-depleted patients.
• Risk of electrolyte imbalances: hypokalemia, hyponatremia, hypomagnesemia.
• Monitor renal function regularly; azilsartan may cause renal impairment in susceptible patients.
• Risk of hyperuricemia and gout exacerbation due to chlorthalidone.
• Use caution in patients with diabetes, as chlorthalidone may impair glucose tolerance.
• Avoid abrupt discontinuation to prevent rebound hypertension.

Common:

• Dizziness, headache
• Fatigue
• Hypotension
• Electrolyte disturbances (hypokalemia, hyponatremia)
• Increased uric acid levels

Serious (Less Common):

• Acute renal failure
• Severe hypotension/syncope
• Hyperkalemia (rare)
• Allergic reactions including rash and photosensitivity
• Electrolyte imbalance-related arrhythmias

• Potassium supplements or potassium-sparing diuretics: Increased risk of hyperkalemia.
• NSAIDs: May reduce antihypertensive effect and worsen renal function.
• Lithium: Increased lithium toxicity risk.
• Other antihypertensives: Additive hypotensive effects.
• CYP2C9 inhibitors: May increase azilsartan levels; monitor patient.

• Combination therapy with ARB and thiazide-like diuretics is recommended in hypertension guidelines for improved blood pressure control.
• Azilsartan + chlorthalidone offers superior blood pressure lowering compared to some other ARB + diuretic combinations.
• Guidelines emphasize monitoring electrolytes and renal function during therapy.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep container tightly closed.
• Avoid freezing.