This combination preparation is indicated for the management of hypertension to effectively lower blood pressure:

• In patients whose blood pressure is not adequately controlled with ARB monotherapy
• As an initial treatment in patients who are likely to require multiple antihypertensive agents
• To achieve target blood pressure levels
• To reduce the risk of both fatal and non-fatal cardiovascular events, particularly stroke and myocardial infarction

This formulation combines an angiotensin II receptor blocker (ARB) with a thiazide-like diuretic for the treatment of hypertension. It is suitable for patients whose blood pressure is not adequately controlled with a single agent or for those who may require combination therapy from the beginning. Lowering blood pressure significantly reduces the risk of cardiovascular complications, including stroke and myocardial infarction. Clinical trials have demonstrated these benefits across different classes of antihypertensive drugs, including ARBs like azilsartan medoxomil and thiazide-like diuretics such as chlorthalidone.

Azilsartan medoxomil is an angiotensin II receptor blocker (ARB) that promotes vasodilation and helps eliminate sodium and water from the body. Chlorthalidone, a thiazide-like diuretic, enhances the excretion of excess salt and water through the kidneys. Together, these agents provide a complementary effect in reducing blood pressure, especially in patients requiring combination therapy.

Absorption: Azilsartan medoxomil is rapidly converted in the gastrointestinal tract to its active form, azilsartan. It is not detectable in plasma after oral administration. The absolute bioavailability of azilsartan is approximately 60%, with peak plasma concentrations occurring within 1.5 to 3 hours. Food does not significantly affect its bioavailability.

Distribution: Azilsartan has a volume of distribution of approximately 16 liters and is highly protein-bound (>99%), primarily to albumin. Chlorthalidone is largely bound to erythrocyte carbonic anhydrase and approximately 75% is protein-bound in plasma, mainly to albumin.

Metabolism and Elimination: Azilsartan is metabolized mainly by CYP2C9 into two metabolites (M-I and M-II), which have minimal or no pharmacological activity. The elimination half-life is about 11 hours, and steady-state levels are achieved within 5 days without accumulation. Chlorthalidone is primarily excreted unchanged via the kidneys. Information regarding non-renal elimination pathways and distribution in body tissues is limited.

The recommended starting dose is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. This combination may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic/diastolic clinic blood pressure reduction of 13/6 mm Hg when switched to this combination 40/12.5 mg.

This combination may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals. Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of this combination. This may be taken with or without food.

Diuretics such as chlorthalidone can reduce the renal clearance of lithium, increasing the risk of lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect and increase the risk of renal impairment when used concurrently.

This combination is contraindicated in patients with anuria.

• Fetal toxicity
• Hypotension (especially in volume- or salt-depleted patients)
• Impaired renal function
• Hypokalemia (low potassium)
• Hyperuricemia (increased uric acid)

• In patients with an activated renin-angiotensin-aldosterone system (RAAS), such as those with volume or salt depletion, this combination may cause excessive hypotension. Any fluid or salt deficiency should be corrected before initiating therapy.
• In patients with renal artery stenosis, this combination may precipitate renal failure. Renal function should be monitored regularly, and discontinuation should be considered if deterioration occurs.
• Caution is also advised in patients with cardiac rhythm disorders (e.g., bradycardia, QT prolongation, ventricular tachycardia), liver disease, electrolyte imbalances (such as low potassium or magnesium), and severe renal impairment.

Combination antihypertensive agents.

Store below 30°C, protected from light and moisture. Keep out of reach of children.